Stable aqueous capsaicin injectable formulations and medical uses thereof

ABSTRACT

The invention provides stable, aqueous capsaicin injectable formulations, a unit dose containing such injectable formulations, medical kits, and methods for using such injectable formulations and unit doses to treat patients suffering from pain, such as osteoarthritic knee pain. The stable, aqueous capsaicin injectable formulations may contain, for example, capsaicin, a solubilizing agent (e.g., a polyethylene glycol ester of a (C15-C25) hydroxyalkanoic acid), an antioxidant, and water.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the national stage application of International(PCT) Patent Application Serial No. PCT/US2017/059628, filed Nov. 2,2017, which claims the benefit of and priority to U.S. ProvisionalPatent Application Ser. No. 62/416,345, filed Nov. 2, 2016, the entirecontents of these applications are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

The invention provides stable, aqueous capsaicin injectableformulations, a unit dose containing such injectable formulations,medical kits, and methods for using such injectable formulations andunit doses to treat patients suffering from pain, such as osteoarthriticknee pain.

BACKGROUND

Pain can function as a protective mechanism that allows healthy humanbeings and animals to avoid tissue damage and/or prevent further damageto injured tissue. However, there are many instances in which painpersists beyond its usefulness. Such unnecessary suffering from pain canimpair a subject's physical mobility, mental performance, and evencontribute to depression.

Substantial resources have been devoted over the years to researchingthe causes of various types of pain and to the development of medicineto attenuate pain experienced by a patient. Exemplary classes of commonpain-relief medications include opioids, non-steroidal anti-inflammatoryagents, corticosteroids, and centrally acting agents such asanti-depressants, anti-epileptics, pregabalin, and gabapentin. Capsaicinhas been described for use in treating pain. See, for example, U.S. Pat.Nos. 5,962,532; 8,420,600; 8,367,733; and 8,158,682. Certain commercialproducts containing capsaicin for pain relief formulate the capsaicin asa cream (e.g., Capzasin) or in a patch (e.g., a capsaicin-containingtransdermal patch marketed under the trade name QUTENZA®) for topicalapplication to the skin of a patient.

Because capsaicin is soluble in organic solvents, but poorly soluble inwater, new formulations are needed for achieving a desirable amount ofcapsaicin dissolved in an aqueous formulation that is suitable forinjection into a patient, and which has suitable stability for use intypical distribution routes for delivering pharmaceutical agents tomedical facilities which typically involve storage of the formulationfor certain lengths of time. The present invention addresses theforegoing need and provides other related advantages.

SUMMARY

The invention provides stable, aqueous capsaicin injectableformulations, a unit dose containing such injectable formulations,medical kits, and methods for using such injectable formulations andunit doses to treat patients suffering from pain, such as osteoarthriticknee pain. The invention is based in part on the discovery that asolubilizing agent containing a polyethylene glycol ester of along-chain hydroxyalkanoic acid or a polyethylene glycol ester of along-chain hydroxyalkenoic acid (such as a mixture containing apolyethylene glycol ester of 12-hydroxystearic acid, a polyethyleneglycol ester of 12-((12-hydroxyoctadecanoyl)oxy)octadecanoic acid, andpolyethylene glycol sold by BASF under the trade name KOLLIPHOR® HS 15)was able to solubilize greater amounts of capsaicin than other testedsolubilizing agents in the aqueous medium at the desired pH range, andyet produced a formulation suitable for injection to a patient and thatis sufficiently stable to storage that it may be used in the typicaldistribution routes for pharmaceutical agents. Further illustrativebenefits of the injectable formulations of the invention are themultiple benefits provided by the above-cited solubilizing agentrelative to use of a polysorbate to create a stable, aqueous capsaicininjectable formulation suitable for administration to a patient. Thesolubilizing agent used in the invention formulations is superiorlycompatible with capsaicin, which improves the stability of theformulation to storage. By contrast, polysorbates, such as Polysorbate80, can have a greater propensity to form peroxides. Such peroxides cancause undesired oxidation of capsaicin, resulting in loss of capsaicinduring storage of the formulation and increase in the amount andidentity of impurities. The solubilizing agent specified above in theformulations of the invention overcomes this deficiency of polysorbate.Accordingly, the formulations provide the benefit that they achieveelevated levels of dissolved capsaicin in an aqueous medium suitable forinjection directly into a patient, and the formulations are stable tostorage.

The stable, aqueous capsaicin injectable formulations described abovefor capsaicin may be used more generally to solubilize a vanilloidreceptor agonist for administration by to a patient by injection orother route. Accordingly, another aspect of the invention provides astable, aqueous injectable formulation containing a vanilloid receptoragonist, such as resiniferatoxin. Such formulations may be used in aunit dose form, in medical kits, and in methods for treating patientssuffering from pain, such as osteoarthritic knee pain.

Various aspects and embodiments of the invention are described infurther detail below. For example, one aspect of the invention providesan aqueous, capsaicin injectable formulation, comprising:

-   -   a. about 0.03% (w/w) to about 0.3% (w/w) of capsaicin;    -   b. about 0.1% (w/w) to about 3% (w/w) of a solubilizing agent,        wherein the solubilizing agent comprises (i) a polyethylene        glycol ester of a (C₁₅-C₂₅) hydroxyalkanoic acid, (ii) a        polyethylene glycol ester of a (C₁₅-C₂₅) hydroxyalkenoic acid,        or (iii) a polyethylene glycol ester of a (C₁₅-C₂₅) alkanoic        acid substituted by a —OC(O)(C₁₄-C₂₄) hydroxyalkyl group;    -   c. about 0.001% (w/w) to about 2% (w/w) of an antioxidant; and    -   d. at least 92% (w/w) water.

More specific embodiments include, for example, formulations where thesolubilizing agent comprises a (C₁₇)hydroxyalkyl-CO₂-(polyethyleneglycolyl)-H, (C₁₇)hydroxyalkyl-CO₂—(C₁₇)alkylene-CO₂-(polyethyleneglycolyl)-H, and polyethylene glycol. In certain embodiments, theformulation may be further characterized according to, for example, itsstability to storage, such as where less than 1% of the capsaicindegrades upon storage of the formulation at 40° C. for 24 weeks.Additional description of injectable formulations is provided in thedetailed description, along with specific illustrative injectableformulations.

Another aspect of the invention provides a unit dosage form comprising aformulation described herein, such as a formulation in any one of Tables1-5. The unit dosage form may be further characterized according to, forexample, the volume of the unit dosage form, such as where the unitdosage form has a volume in the range of about 0.5 mL to about 3 mL, ormore preferably about 2 mL.

Another aspect of the invention provides a method of treating pain in apatient, where the method comprises administering to a patient in needthereof a therapeutically effective amount of a formulation describedherein, such as a formulation in any one of Tables 1-5, to a site at ornear the location of pain, in order to treat the pain. The pain may bejoint pain, such as where the joint is a knee joint, hip joint, shoulderjoint, elbow joint, carpal joint, tarsal joint, or metatarsal joint. Incertain embodiments, the joint is affected by osteoarthritis. In apreferred embodiment, the pain is pain in a knee joint affected byosteoarthritis. In other embodiments, the pain is pain in or around softtissue.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides stable, aqueous capsaicin injectableformulations, a unit dose containing such injectable formulations,medical kits, and methods for using such injectable formulations andunit doses to treat patients suffering from pain, such as osteoarthriticknee-joint pain. The invention is based in part on the discovery that asolubilizing agent containing a polyethylene glycol ester of along-chain hydroxyalkanoic acid or a polyethylene glycol ester of along-chain hydroxyalkenoic acid (such as a mixture containing apolyethylene glycol ester of 12-hydroxystearic acid, a polyethyleneglycol ester of 12-((12-hydroxyoctadecanoyl)oxy)octadecanoic acid, andpolyethylene glycol sold by BASF under the tradename KOLLIPHOR® HS 15)was able to solubilize greater amounts of capsaicin than other testedsolubilizing agents in the aqueous medium at the desired pH range, andyet produced a formulation suitable for injection to a patient and thatis sufficiently stable to storage that it may be used in the typicaldistribution routes for pharmaceutical agents. Further illustrativebenefits of the injectable formulations of the invention are themultiple benefits provided by the above-cited solubilizing agentrelative to use of a polysorbate to create a stable, aqueous capsaicininjectable formulation suitable for administration to a patient. Thesolubilizing agent used in the invention formulations is superiorlycompatible with capsaicin, which improves the stability of theformulation to storage. By contrast, polysorbates, such as Polysorbate80, can have a greater propensity to form peroxides. Such peroxides cancause undesired oxidation of capsaicin, resulting in loss of capsaicinduring storage of the formulation and increase in the amount andidentity of impurities. The solubilizing agent specified above in theformulations of the invention overcomes this deficiency of polysorbate.Accordingly, the formulations provide the benefit that they achieveelevated levels of dissolved capsaicin in an aqueous medium suitable forinjection directly into a patient, and the formulations are stable tostorage.

The stable, aqueous capsaicin injectable formulations described abovefor capsaicin may be used more generally to solubilize a vanilloidreceptor agonist for administration by injection or other route.Accordingly, another aspect of the invention provides a stable, aqueousinjectable formulation containing a vanilloid receptor agonist, such asresiniferatoxin. Such formulations may be used in a unit dose form, inmedical kits, and in methods for treating patients suffering from pain,such as osteoarthritic knee pain.

Various aspects of the invention are set forth below in sections;however, aspects of the invention described in one particular sectionare not to be limited to any particular section.

I. Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The terms “a” and “an” as used herein mean “one or more” and include theplural unless the context is inappropriate.

The term “about” means within 10% of the stated value. In certainembodiments, the value may be within 8%, 6%, 4%, 2%, or 1% of the statedvalue.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-12,1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂alkyl,C₁-C₁₀alkyl, and C₁-C₆alkyl, respectively. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,etc.

The term “hydroxyalkyl” refers to an alkyl group substituted by 1 or 2hydroxyl groups. In certain embodiments, the hydroxyalkyl is an alkylgroup substituted by only 1 hydroxyl group.

The term “hydroxyalkanoic acid” refers to saturated straight or branchedhydrocarbon that is substituted by (i) one —CO₂H group, and (ii) one ortwo hydroxyl groups.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms,referred to herein as C₂-C₁₂alkenyl, C₂-C₁₀alkenyl, and C₂-C₆alkenyl,respectively. Exemplary alkenyl groups include vinyl, allyl, butenyl,pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, and the like.

The term “hydroxyalkenyl” refers to an alkenyl group substituted by 1 or2 hydroxyl groups. In certain embodiments, the hydroxyalkenyl is analkenyl group substituted by only 1 hydroxyl group.

The term “hydroxyalkenoic acid” refers to an unsaturated straight orbranched hydrocarbon having one carbon-carbon double bond, wherein thehydrocarbon is substituted by (i) one —CO₂H group, and (ii) one or twohydroxyl groups.

The term “polyethylene glycolyl” refers to a radical of polyethyleneglycol. The polyethylene glycolyl is a chemical fragment that is part ofa larger molecule. When the polyethylene glycolyl is bonded at onelocation to the remainder of the molecule, then the polyethyleneglycolyl is a mono-radical, such as “—(CH₂CH₂O)x-H” where x is aninteger greater than 1. When the polyethylene glycolyl is used as acomponent within a molecule connecting two fragments of the molecule,the polyethylene glycolyl is a diradical, having a point of attachmentat each terminus of the polyethylene glycolyl, which may be illustratedas “—(CH₂CH₂O)x-” where x is an integer greater than 1. In certainembodiments, x is an integer in the range of about 5 to about 100, about5 to about 50, about 5 to about 25, about 5 to about 15, about 10 toabout 50, about 10 to about 30, or about 10 to about 20. In certainembodiments, x is about 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19. Incertain preferred embodiments, x is about 15.

Macrogol 15 hydroxystearate has CAS Registry No 70142-34-6, and is amixture containing (a) about 70% (w/w) of a mixture of

and (b) about 30% (w/w) polyethylene glycol; where the polyethyleneglycolyl has a weight-average molecular weight of about 660 g/mol; whichis sold and marketed by BASF as KOLLIPHOR® HS 15.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly. It is understood that graphical depictions ofchemical structures, e.g., generic chemical structures, encompass allstereoisomeric forms of the specified compounds, unless indicatedotherwise.

Individual stereoisomers of compounds of the present invention can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers bywell-known methods, such as chiral-phase gas chromatography,chiral-phase high performance liquid chromatography, crystallizing thecompound as a chiral salt complex, or crystallizing the compound in achiral solvent. Specific stereoisomers can also be obtained selectivelyusing stereomerically pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

Geometric isomers can also exist in the compounds of the presentinvention. The symbol ═ denotes a bond that may be a single, double ortriple bond as described herein. The present invention encompasses thevarious geometric isomers and mixtures thereof resulting from thearrangement of substituents around a carbon-carbon double bond orarrangement of substituents around a carbocyclic ring. Substituentsaround a carbon-carbon double bond are designated as being in the “Z” or“E” configuration wherein the terms “Z” and “E” are used in accordancewith IUPAC standards. Unless otherwise specified, structures depictingdouble bonds encompass both the “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

As used herein, the terms “subject” and “patient” refer to organisms tobe treated by the methods of the present invention. Such organisms arepreferably mammals (e.g., murines, simians, equines, bovines, porcines,canines, felines, and the like), and more preferably humans.

As used herein, the term “effective amount” refers to the amount of acompound (e.g., a compound of the present invention) sufficient toeffect beneficial or desired results. An effective amount can beadministered in one or more administrations, applications or dosages andis not intended to be limited to a particular formulation oradministration route. As used herein, the term “treating” includes anyeffect, e.g., lessening, reducing, modulating, ameliorating oreliminating, that results in the improvement of the condition, disease,disorder, and the like, or ameliorating a symptom thereof.

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metal (e.g.,sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides,ammonia, and compounds of formula NW₃, wherein W is C₁₋₄ alkyl, and thelike.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na⁺, NH₄ ⁺, and NW₄⁺ (wherein W is a C₁₋₄ alkyl group), and the like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified. Further, if a variable is not accompanied bya definition, then the previous definition of the variable controls.

II. Aqueous Injectable Formulations

One aspect of the invention provides aqueous, injectable formulations.The formulations provide the benefits that they are stable to storageand can be administered directly to a patient via injection. Theformulations contain a solubilizing agent to achieve the desired higherconcentration of vanilloid receptor agonist in the aqueous medium. Theformulations are particularly useful for administering capsaicin byinjection to a patient.

As indicated above, the invention is based in part on the discovery thata solubilizing agent containing a polyethylene glycol ester of along-chain hydroxyalkanoic acid or a polyethylene glycol ester of along-chain hydroxyalkenoic acid (such as a mixture containing apolyethylene glycol ester of 12-hydroxystearic acid, a polyethyleneglycol ester of 12-((12-hydroxyoctadecanoyl)oxy)octadecanoic acid, andpolyethylene glycol sold by BASF under the trade name KOLLIPHOR® HS 15)was able to solubilize greater amounts of capsaicin than other testedsolubilizing agents in the aqueous medium at the desired pH range, andyet produced a formulation suitable for injection to a patient and thatis sufficiently stable to storage that it may be used in the typicaldistribution routes for pharmaceutical agents. Further illustrativebenefits of the injectable formulations of the invention are themultiple benefits provided by the above-cited solubilizing agentrelative to use of a polysorbate to create a stable, aqueous capsaicininjectable formulation suitable for administration to a patient. Thesolubilizing agent used in the invention formulations is superiorlycompatible with capsaicin, which improves the stability of theformulation to storage. By contrast, polysorbates, such as Polysorbate80, can have a greater propensity to form peroxides. Such peroxides cancause undesired oxidation of capsaicin, resulting in loss of capsaicinduring storage of the formulation and increase in the amount andidentity of impurities. The solubilizing agent specified above in theformulations of the invention overcomes this deficiency of polysorbate.Additionally, the solubilizing agent used in the invention formulationsovercomes the adverse side effect of polysorbates, such as Polysorbate80, of triggering release of histamine when administered to a patient.Accordingly, the specific solubilizing agent described herein for use inthe invention formulations imparts multiple benefits.

Additional features of the aqueous injectable formulations are describedbelow.

One aspect of the invention provides an aqueous, capsaicin injectableformulation, wherein the formulation comprises

-   -   a. about 0.03% (w/w) to about 0.3% (w/w) of capsaicin;    -   b. about 0.1% (w/w) to about 3% (w/w) of a solubilizing agent,        wherein the solubilizing agent comprises (i) a polyethylene        glycol ester of a (C₁₅-C₂₅) hydroxyalkanoic acid, (ii) a        polyethylene glycol ester of a (C₁₅-C₂₅) hydroxyalkenoic acid,        or (iii) a polyethylene glycol ester of a (C₁₅-C₂₅) alkanoic        acid substituted by a —OC(O)(C₁₄-C₂₄) hydroxyalkyl group;    -   c. about 0.001% (w/w) to about 2% (w/w) of an antioxidant; and    -   d. at least 92% (w/w) water.

Another aspect of the invention provides an aqueous, capsaicininjectable formulation, wherein the formulation comprises

-   -   a. about 0.01% (w/w) to about 0.5% (w/w) of capsaicin;    -   b. about 0.01% (w/w) to about 5% (w/w) of a solubilizing agent,        wherein the solubilizing agent comprises (i) a polyethylene        glycol ester of a (C₁₅-C₂₅) hydroxyalkanoic acid, (ii) a        polyethylene glycol ester of a (C₁₅-C₂₅) hydroxyalkenoic acid,        or (iii) a polyethylene glycol ester of a (C₁₅-C₂₅) alkanoic        acid substituted by a —OC(O)(C₁₄-C₂₄) hydroxyalkyl group; and    -   c. water.

Another aspect of the invention provides an aqueous, vanilloid receptoragonist injectable formulation, wherein the formulation comprises

-   -   a. a vanilloid receptor agonist (e.g., about 0.001% (w/w) to        about 5% (w/w) of the vanilloid receptor agonist);    -   b. about 0.01% (w/w) to about 5% (w/w) of a solubilizing agent,        wherein the solubilizing agent comprises (i) a polyethylene        glycol ester of a (C₁₅-C₂₅) hydroxyalkanoic acid, (ii) a        polyethylene glycol ester of a (C₁₅-C₂₅) hydroxyalkenoic acid,        or (iii) a polyethylene glycol ester of a (C₁₅-C₂₅) alkanoic        acid substituted by a —OC(O)(C₁₄-C₂₄) hydroxyalkyl group; and    -   c. water.

Another aspect of the invention provides an aqueous, capsaicininjectable formulation, wherein the formulation comprises

-   -   a. about 0.03% (w/w) to about 0.3% (w/w) of capsaicin;    -   b. about 0.1% (w/w) to about 3% (w/w) of a solubilizing agent,        wherein the solubilizing agent comprises (i) a polyethylene        glycol ester of a (C₁₅-C₂₅) hydroxyalkanoic acid, (ii) a        polyethylene glycol ester of a (C₁₅-C₂₅) hydroxyalkenoic acid,        or (iii) a polyethylene glycol ester of a (C₁₅-C₂₅) alkanoic        acid substituted by a —OC(O)(C₁₄-C₂₄) hydroxyalkyl group; and    -   c. at least 92% (w/w) water.

Another aspect of the invention provides an aqueous, capsaicininjectable formulation, wherein the formulation comprises

-   -   a. about 0.03% (w/w) to about 0.1% (w/w) of capsaicin;    -   b. about 0.5% (w/w) to about 1.5% (w/w) of a solubilizing agent,        wherein the solubilizing agent comprises (i) a polyethylene        glycol ester of a (C₁₅-C₂₅) hydroxyalkanoic acid, or (ii) a        polyethylene glycol ester of a (C₁₅-C₂₅) alkanoic acid        substituted by a —OC(O)(C₁₄-C₂₄) hydroxyalkyl group; and    -   c. at least 92% (w/w) water.

Exemplary components and features of the aqueous injectable formulationsare described in more detail below.

Amount of Solubilizing Agent

The formulation can be further characterized according to the amount ofsolubilizing agent in the formulation. For example, in certainembodiments, the formulation comprises about 0.5% (w/w) to about 1.5%(w/w) of the solubilizing agent. In certain other embodiments, theformulation comprises about 0.8% (w/w) to about 1.2% (w/w) of thesolubilizing agent. In certain other embodiments, the formulationcomprises about 1% (w/w) of the solubilizing agent. In certain otherembodiments, the formulation comprises about 1.5% (w/w) to about 2.5%(w/w) of the solubilizing agent. In certain other embodiments, theformulation comprises about 2% (w/w) of the solubilizing agent.

Identity of Solubilizing Agent

The formulation can be further characterized according to the identityof the solubilizing agent in the formulation. For example, in certainembodiments, the solubilizing agent comprises (i) a polyethylene glycolester of a (C₁₅-C₂₅) hydroxyalkanoic acid, or (ii) a polyethylene glycolester of a (C₁₅-C₂₅) hydroxyalkenoic acid. In certain embodiments, thesolubilizing agent comprises a (C₁₄-C₂₄)hydroxyalkyl-CO₂-(polyethyleneglycolyl)-H and(C₁₄-C₂₄)hydroxyalkyl-CO₂—(C₁₄-C₂₄)alkylene-CO₂-(polyethyleneglycolyl)-H. In certain embodiments, the solubilizing agent comprises a(C₁₄-C₂₄)hydroxyalkyl-CO₂-(polyethylene glycolyl)-H,(C₁₄-C₂₄)hydroxyalkyl-CO₂—(C₁₄-C₂₄)alkylene-CO₂-(polyethyleneglycolyl)-H, and polyethylene glycol. In certain embodiments, thesolubilizing agent comprises (a) from about 60% (w/w) to about 80% (w/w)of a mixture of (C₁₄-C₂₄)hydroxyalkyl-CO₂-(polyethylene glycolyl)-H and(C₁₄-C₂₄)hydroxyalkyl-CO₂—(C₁₄-C₂₄)alkylene-CO₂-(polyethyleneglycolyl)-H, and (b) from about 20% (w/w) to about 40% (w/w)polyethylene glycol. In certain embodiments, the solubilizing agentcomprises (a) about 70% (w/w) of a mixture of(C₁₄-C₂₄)hydroxyalkyl-CO₂-(polyethylene glycolyl)-H and(C₁₄-C₂₄)hydroxyalkyl-CO₂—(C₁₄-C₂₄)alkylene-CO₂-(polyethyleneglycolyl)-H, and (b) about 30% (w/w) polyethylene glycol. In certainembodiments, the solubilizing agent is a mixture of(C₁₄-C₂₄)hydroxyalkyl-CO₂-(polyethylene glycolyl)-H,(C₁₄-C₂₄)hydroxyalkyl-CO₂—(C₁₄-C₂₄)alkylene-CO₂-(polyethyleneglycolyl)-H, and polyethylene glycol. In certain embodiments, thesolubilizing agent is a mixture of (a) from about 60% (w/w) to about 80%(w/w) of a mixture of (C₁₄-C₂₄)hydroxyalkyl-CO₂-(polyethyleneglycolyl)-H and(C₁₄-C₂₄)hydroxyalkyl-CO₂—(C₁₄-C₂₄)alkylene-CO₂-(polyethyleneglycolyl)-H, and (b) from about 20% (w/w) to about 40% (w/w)polyethylene glycol. In certain embodiments, the solubilizing agent is amixture of (a) about 70% (w/w) of a mixture of(C₁₄-C₂₄)hydroxyalkyl-CO₂-(polyethylene glycolyl)-H and(C₁₄-C₂₄)hydroxyalkyl-CO₂—(C₁₄-C₂₄)alkylene-CO₂-(polyethyleneglycolyl)-H, and (b) about 30% (w/w) polyethylene glycol.

In certain embodiments, the solubilizing agent comprises (a) apolyethylene glycol ester of a (C₁₅-C₂₅) hydroxyalkanoic acid and (b) apolyethylene glycol ester of a (C₁₅-C₂₅) alkanoic acid substituted by a—OC(O)(C₁₄-C₂₄) hydroxyalkyl group, wherein the mole ratio of (a) to (b)is in the range of 10:1 to 1:10, 5:1 to 1:5, 2:1 to 1:2, 10:1 to 5:1,5:1 to 2:1, 2:1 to 1:1, 1:1 to 1:2, 1:2 to 1:5, 1:5 to 1:10, or isgreater than 10:1, or less than 1:1.

In a more specific embodiment, the solubilizing agent comprises a(C₁₇)hydroxyalkyl-CO₂-(polyethylene glycolyl)-H and(C₁₇)hydroxyalkyl-CO₂—(C₁₇)alkylene-CO₂-(polyethylene glycolyl)-H. Incertain embodiments, the solubilizing agent comprises a(C₁₇)hydroxyalkyl-CO₂-(polyethylene glycolyl)-H,(C₁₇)hydroxyalkyl-CO₂—(C₁₇)alkylene-CO₂-(polyethylene glycolyl)-H, andpolyethylene glycol. In certain embodiments, the solubilizing agentcomprises (a) from about 60% (w/w) to about 80% (w/w) of a mixture of(C₁₇)hydroxyalkyl-CO₂-(polyethylene glycolyl)-H and(C₁₇)hydroxyalkyl-CO₂—(C₁₇)alkylene-CO₂-(polyethylene glycolyl)-H, and(b) from about 20% (w/w) to about 40% (w/w) polyethylene glycol. Incertain embodiments, the solubilizing agent comprises (a) about 70%(w/w) of a mixture of (Cr)hydroxyalkyl-CO₂-(polyethylene glycolyl)-H and(C₁₇)hydroxyalkyl-CO₂—(C₁₇)alkylene-CO₂-(polyethylene glycolyl)-H, and(b) about 30% (w/w) polyethylene glycol. In certain embodiments, thesolubilizing agent is a mixture of (a) from about 60% (w/w) to about 80%(w/w) of a mixture of (C₁₇)hydroxyalkyl-CO₂-(polyethylene glycolyl)-Hand (C₁₇)hydroxyalkyl-CO₂—(C₁₇)alkylene-CO₂-(polyethylene glycolyl)-H,and (b) from about 20% (w/w) to about 40% (w/w) polyethylene glycol. Incertain embodiments, the solubilizing agent is a mixture of (a) about70% (w/w) of a mixture of (C₁₇)hydroxyalkyl-CO₂-(polyethyleneglycolyl)-H and (C₁₇)hydroxyalkyl-CO₂—(C₁₇)alkylene-CO₂-(polyethyleneglycolyl)-H, and (b) about 30% (w/w) polyethylene glycol.

In certain embodiments, the mole ratio of (a)(C₁₄-C₂₄)hydroxyalkyl-CO₂-(polyethylene glycolyl)-H to (b)(C₁₄-C₂₄)hydroxyalkyl-CO₂—(C₁₄-C₂₄)alkylene-CO₂-(polyethyleneglycolyl)-H in the formulation is in the range of 10:1 to 1:10, 5:1 to1:5, 2:1 to 1:2, 10:1 to 5:1, 5:1 to 2:1, 2:1 to 1:1, 1:1 to 1:2, 1:2 to1:5, 1:5 to 1:10, or is greater than 10:1, or less than 1:1. In certainembodiments, the mole ratio of (a) (C₁₇)hydroxyalkyl-CO₂-(polyethyleneglycolyl)-H to (b) (C₁₇)hydroxyalkyl-CO₂—(C₁₇)alkylene-CO₂-(polyethyleneglycolyl)-H in the formulation is in the range of 10:1 to 1:10, 5:1 to1:5, 2:1 to 1:2, 10:1 to 5:1, 5:1 to 2:1, 2:1 to 1:1, 1:1 to 1:2, 1:2 to1:5, 1:5 to 1:10, or is greater than 10:1, or less than 1:1.

In a more specific embodiment, the solubilizing agent comprises

In another more specific embodiment, the solubilizing agent is a mixtureof

and polyethylene glycol. In certain other embodiments, the solubilizingagent comprises (a) about 70% (w/w) of a mixture

and (b) about 30% (w/w) polyethylene glycol. In certain otherembodiments, the solubilizing agent is a mixture of (a) about 70% (w/w)of a mixture of

and (b) about 30% (w/w) polyethylene glycol. In certain otherembodiments, the solubilizing agent comprises (a) from 68% (w/w) to 72%(w/w) of a mixture of

and (b) from 28% (w/w) to 32% (w/w) polyethylene glycol.

In certain embodiments, the mole ratio of (a)

in the formulation is in the range of 10:1 to 1:10, 5:1 to 1:5, 2:1 to1:2, 10:1 to 5:1, 5:1 to 2:1, 2:1 to 1:1, 1:1 to 1:2, 1:2 to 1:5, 1:5 to1:10, or is greater than 10:1, or less than 1:1.

The above solubilizing agent can be further characterized according tothe weight-average molecular weight of any polyethylene glycolylcomponent. For example, in certain embodiments, the polyethyleneglycolyl has a weight-average molecular weight in the range of about 100g/mol to about 3000 g/mol. In certain embodiments, the polyethyleneglycolyl has a weight-average molecular weight in the range of about 200g/mol to about 1500 g/mol. In certain embodiments, the polyethyleneglycolyl has a weight-average molecular weight in the range of about 200g/mol to about 1000 g/mol. In certain embodiments, the polyethyleneglycolyl has a weight-average molecular weight in the range of about 300g/mol to about 900 g/mol. In certain embodiments, the polyethyleneglycolyl has a weight-average molecular weight in the range of about 500g/mol to about 800 g/mol. In certain embodiments, the polyethyleneglycolyl has a weight-average molecular weight in the range of about 600g/mol to about 750 g/mol. In certain embodiments, the polyethyleneglycolyl has a weight-average molecular weight in the range of about 600g/mol to about 700 g/mol. In certain embodiments, the polyethyleneglycolyl has a weight-average molecular weight of about 660 g/mol. Incertain embodiments, the polyethylene glycolyl has a weight-averagemolecular weight in the range of about 100 g/mol to about 300 g/mol,about 300 g/mol to about 500 g/mol, about 500 g/mol to about 1000 g/mol,about 1000 g/mol to about 1500 g/mol, about 1500 g/mol to about 2000g/mol, or about 2000 g/mol to about 2500 g/mol.

The above solubilizing agent can be further characterized according tothe weight-average molecular weight of any polyethylene glycolcomponent. For example, in certain embodiments, the polyethylene glycolhas a weight-average molecular weight in the range of about 100 g/mol toabout 3000 g/mol. In certain embodiments, the polyethylene glycol has aweight-average molecular weight in the range of about 200 g/mol to about1500 g/mol. In certain embodiments, the polyethylene glycol has aweight-average molecular weight in the range of about 200 g/mol to about1000 g/mol. In certain embodiments, the polyethylene glycol has aweight-average molecular weight in the range of about 300 g/mol to about900 g/mol. In certain embodiments, the polyethylene glycol has aweight-average molecular weight in the range of about 500 g/mol to about800 g/mol. In certain embodiments, the polyethylene glycol has aweight-average molecular weight in the range of about 600 g/mol to about750 g/mol. In certain embodiments, the polyethylene glycol has aweight-average molecular weight in the range of about 600 g/mol to about700 g/mol. In certain embodiments, the polyethylene glycol has aweight-average molecular weight of about 660 g/mol. In certainembodiments, the polyethylene glycol has a weight-average molecularweight in the range of about 100 g/mol to about 300 g/mol, about 300g/mol to about 500 g/mol, about 500 g/mol to about 1000 g/mol, about1000 g/mol to about 1500 g/mol, about 1500 g/mol to about 2000 g/mol, orabout 2000 g/mol to about 2500 g/mol.

In yet other embodiments, any polyethylene glycol or polyethyleneglycolyl each independently have a weight-average molecular weight inthe range of about 100 g/mol to about 3000 g/mol. In certainembodiments, any polyethylene glycol or polyethylene glycolyl eachindependently have a weight-average molecular weight in the range ofabout 200 g/mol to about 1500 g/mol. In certain embodiments, anypolyethylene glycol or polyethylene glycolyl each independently have aweight-average molecular weight in the range of about 200 g/mol to about1000 g/mol. In certain embodiments, any polyethylene glycol orpolyethylene glycolyl each independently have a weight-average molecularweight in the range of about 300 g/mol to about 900 g/mol. In certainembodiments, any polyethylene glycol or polyethylene glycolyl eachindependently have a weight-average molecular weight in the range ofabout 500 g/mol to about 800 g/mol. In certain embodiments, anypolyethylene glycol or polyethylene glycolyl each independently have aweight-average molecular weight in the range of about 600 g/mol to about750 g/mol. In certain embodiments, any polyethylene glycol orpolyethylene glycolyl each independently have a weight-average molecularweight in the range of about 600 g/mol to about 700 g/mol. In certainembodiments, any polyethylene glycol or polyethylene glycolyl eachindependently have a weight-average molecular weight of about 660 g/mol.In certain embodiments, any polyethylene glycol or polyethylene glycolyleach independently have a weight-average molecular weight in the rangeof about 100 g/mol to about 300 g/mol, about 300 g/mol to about 500g/mol, about 500 g/mol to about 1000 g/mol, about 1000 g/mol to about1500 g/mol, about 1500 g/mol to about 2000 g/mol, or about 2000 g/mol toabout 2500 g/mol.

Antioxidant

The formulation can be further characterized according to theantioxidant in the formulation. For example, in certain embodiments, theformulation comprises about 0.005% (w/w) to about 0.1% (w/w) of anantioxidant. In certain embodiments, the formulation comprises about0.01% (w/w) of an antioxidant. In certain embodiments, the antioxidantis an organic compound. In certain embodiments, the antioxidant is asubstituted phenol. In certain embodiments, the antioxidant is aphenolic antioxidant. In certain embodiments, the antioxidant isdibutylhydroxytoluene.

Chelating Agent

The formulation may optionally further comprise a chelating agent.Accordingly, in certain embodiments, the formulation further comprises achelating agent. In certain embodiments, the formulation comprises about0.001% (w/w) to about 0.5% (w/w) of a chelating agent. In certainembodiments, the formulation comprises about 0.01% (w/w) to about 0.05%(w/w) of a chelating agent. In certain embodiments, the formulationcomprises about 0.025% (w/w) of a chelating agent.

Exemplary chelating agents include, but are not limited to,ethylenediaminetetraacetic acid (EDTA), citric acid, sorbitol, tartaricacid, phosphoric acid, salts of the foregoing, and the like. In certainembodiments, the chelating agent is an aliphatic amine compoundcontaining at least two carboxylic acid groups. In certain embodiments,the chelating agent is ethylenediaminetetraacetic acid or a saltthereof.

In certain embodiments, the chelating agent is a metal ion chelatingagent.

In certain embodiments, the combination of an antioxidant and achelating agent (e.g., ethylenediaminetetraacetic acid or salt thereof)can increase the stability of an aqueous capsaicin formulation.

Buffer

The formulation may optionally further comprise a buffer. The bufferhelps reduce changes in pH of the formulation over time and may provideimproved drug stability. Exemplary buffers include, but are not limitedto, sodium bicarbonate, sodium citrate, citric acid, sodium phosphate,pharmaceutically acceptable salts thereof, and combinations thereof. Incertain embodiments, the buffer is an acetate salt, phosphate salt,citrate salt; corresponding acids of the foregoing; and combinations ormixtures thereof.

Accordingly, in certain embodiments, the formulation further comprises abuffer. In certain embodiments, the buffer comprises a carboxylic acidcompound having a molecular weight less than 500 g/mol, a salt thereof,or a mixture thereof. In certain embodiments, the buffer comprises aC₁-C₆ alkanoic acid, a salt thereof, or a mixture thereof. In certainembodiments, the buffer comprises acetic acid, a salt of acetic acid, ora mixture thereof. In certain embodiments, the buffer is a mixture ofalkali metal acetate and acetic acid. In certain embodiments, the bufferis a mixture of sodium acetate and acetic acid.

In certain embodiments, the formulation comprises about 0.1% (w/w) toabout 1.0% (w/w) of a buffer. In certain embodiments, the formulationcomprises about 0.5% (w/w) to about 0.8% (w/w) of a buffer. In certainembodiments, the formulation comprises about 0.7% (w/w) of a buffer. Theamount of buffer may be alternatively characterized according to themolarity of the buffer in the formulation. Accordingly, in certainembodiments, the formulation comprises about 10 mM to about 100 mM of abuffer. In certain embodiments, the formulation comprises about 25 mM toabout 75 mM of a buffer. In certain embodiments, the formulationcomprises about 50 mM of a buffer (which preferably is a mixture of analkali metal acetate and acetic acid, such as a mixture of sodiumacetate and acetic acid).

Osmolality

The formulation may be further characterized according to the osmolalityof the formulation. Formulations having an osmolality at or near theosmolality of a typical bodily fluid are referred to as isotonic.Formulations having an osmolality greater than the osmolality of atypical bodily fluid are referred to as hypertonic. Formulations havingan osmolality less than the osmolality of a typical bodily fluid arereferred to as hypotonic.

The osmolality of the formulation may be optionally adjusted byincluding a tonicity modifier. Accordingly, in certain embodiments, theformulation further comprises a tonicity modifier. In certainembodiments, the formulation comprises about 0.01% (w/w) to about 5%(w/w) of a tonicity modifier. In certain embodiments, the formulationcomprises about 0.1% (w/w) to about 2% (w/w) of a tonicity modifier. Incertain embodiments, the formulation comprises about 0.3% (w/w) to about0.9% (w/w) of a tonicity modifier. In certain embodiments, theformulation comprises about 0.6% (w/w) of a tonicity modifier (whichpreferably is an alkali metal halide, such as sodium chloride).

In certain embodiments, the tonicity modifier is an alkali metal salt.In certain embodiments, the tonicity modifier is sodium chloride. Incertain embodiments, the tonicity modifier is a monosaccharide. Incertain embodiments, the tonicity modifier is dextrose.

Formulations may be characterized according to an osmolality thresholdor range. For example, in certain embodiments, the formulation may havean osmolality of at least 200 mOsm/kg, 220 mOsm/kg, 240 mOsm/kg, 260mOsm/kg, 280 mOsm/kg, 300 mOsm/kg, 325 mOsm/kg, 350 mOsm/kg, 375mOsm/kg, 400 mOsm/kg, 425 mOsm/kg, 450 mOsm/kg, 500 mOsm/kg, 600mOsm/kg, 700 mOsm/kg, 800 mOsm/kg, 900 mOsm/kg, or 1000 mOsm/kg. Incertain embodiments, the formulation has an osmolality of at least 240mOsm/kg. In certain embodiments, the formulation has an osmolality of atleast 270 mOsm/kg.

In certain embodiments, the formulation has an osmolality in the rangeof from about 200 mOsm/kg to about 400 mOsm/kg, from about 240 mOsm/kgto about 350 mOsm/kg, from about 240 mOsm/kg to about 340 mOsm/kg, fromabout 270 mOsm/kg to about 340 mOsm/kg, from about 270 mOsm/kg to about330 mOsm/kg, from about 270 mOsm/kg to about 310 mOsm/kg, from about 290mOsm/kg to about 330 mOsm/kg, from about 280 mOsm/kg to about 300mOsm/kg, or from about 300 mOsm/kg to about 320 mOsm/kg. In certainembodiments, the formulation has an osmolality in the range of fromabout 240 mOsm/kg to about 340 mOsm/kg. In certain other embodiments,the formulation has an osmolality in the range from about 270 mOsm/kg toabout 330 mOsm/kg.

In certain embodiments, the formulation has osmolality of about 200mOsm/kg, about 220 mOsm/kg, about 240 mOsm/kg, about 250 mOsm/kg, about260 mOsm/kg, about 270 mOsm/kg, about 280 mOsm/kg, about 290 mOsm/kg,about 300 mOsm/kg, about 310 mOsm/kg, about 320 mOsm/kg, about 330mOsm/kg, about 340 mOsm/kg, about 350 mOsm/kg, about 360 mOsm/kg, about370 mOsm/kg, or about 380 mOsm/kg. In a preferred embodiment, theformulation has osmolality of about 290 mOsm/kg. In another preferredembodiment, the formulation has osmolality of about 310 mOsm/kg.

Amount of Water

The formulation may be further characterized according to the amount ofwater in the formulation. For example, in certain embodiments, theformulation comprises at least 95% (w/w) water. In certain embodiments,the formulation comprises at least 97% (w/w) water. In certainembodiments, the formulation comprises from about 95% (w/w) to about 99%(w/w) water. In certain embodiments, the formulation comprises fromabout 97% (w/w) to about 98% (w/w) water. In certain embodiments, theformulation comprises from about 93% (w/w) to about 96% (w/w) water.

pH of the Formulation

The formulation may be further characterized according to the pH of theformulation. For example, in certain embodiments, the formulation has apH in the range of about 4 to about 7. In certain embodiments, theformulation has a pH in the range of about 5 to about 6. In certainembodiments, the formulation has a pH in the range of about 5.0 to about5.2, about 5.2 to about 5.4, about 5.4 to about 5.6, or about 5.6 toabout 5.8. In certain embodiments, the formulation has a pH of about5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, or 5.9. In certain embodiments,the formulation has a pH of about 5.5.

Vanilloid Receptor Agonist

For a formulation containing a vanilloid receptor agonist, theformulation may be further characterized according to the amount andidentity of the vanilloid receptor agonist. For example, in certainembodiments, the formulation comprises from about 0.001% (w/w) to about5% (w/w), from about 0.001% (w/w) to about 1% (w/w), or from about 0.01%(w/w) to about 0.1% (w/w) of vanilloid receptor agonist. Exemplaryvanilloid receptor agonists include, for example, capsaicin,resiniferatoxin, N-vanillylnonanamides, N-vanillylsulfonamides,N-vanillylureas, N-vanillylcarbamates, N-[(substitutedphenyl)methyl]alkylamides, methylene substituted N-[(substitutedphenyl)methyl]alkanamides, N-[(substitutedphenyl)methyl]-cis-monosaturated alkenamides, N-[(substitutedphenyl)methyl]diunsaturated amides, 3-hydroxyacetanilide,hydroxyphenylacetamides, pseudocapsaicin, dihydrocapsaicin,nordihydrocapsaicin anandamide, piperine, zingerone, warburganal,polygodial, aframodial, cinnamodial, cinnamosmolide, cinnamolide,isovelleral, scalaradial, ancistrodial, beta-acaridial, merulidial, andscutigeral.

Capsaicin

Capsaicin has the chemical nameN-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide, and due tothe presence of a carbon-carbon double bond can exist as a mixture ofcis and trans isomers. The formulations may be characterized accordingto the isomeric purity of the capsaicin administered to the patient. Forexample, in certain embodiments, the capsaicin is a mixture ofcis-capsaicin and trans-capsaicin that contains at least 95% by weighttrans-capsaicin. In certain embodiments, the capsaicin is a mixture ofcis-capsaicin and trans-capsaicin that contains at least 97% by weighttrans-capsaicin. In certain embodiments, the capsaicin is a mixture ofcis-capsaicin and trans-capsaicin that contains at least 98% by weighttrans-capsaicin. In certain embodiments, the capsaicin is a mixture ofcis-capsaicin and trans-capsaicin that contains at least 99% by weighttrans-capsaicin. In certain other embodiments, the capsaicin is amixture of cis-capsaicin and trans-capsaicin that contains at least 95%by weight cis-capsaicin. Accordingly, formulations described hereincontaining capsaicin can be characterized according to the isomericpurity of the capsaicin.

The isomeric purity of capsaicin may also be expressed according to themolar ratio of trans vs. cis isomer. Accordingly, in certainembodiments, the capsaicin is present as a mixture of trans and cisisomers, wherein the ratio of trans:cis isomers is at least 10:1. Incertain embodiments, the ratio of trans:cis isomers is at least 15:1. Incertain embodiments, the capsaicin consists essentially of the transisomer.

The formulation may be further characterized according to the amount ofcapsaicin in the formulation. For example, in certain embodiments, theformulation comprises from about 0.03% (w/w) to about 0.15% (w/w) ofcapsaicin. In certain embodiments, the formulation comprises from about0.03% (w/w) to about 0.07% (w/w) of capsaicin. In certain embodiments,the formulation comprises from about 0.01% (w/w) to about 0.03% (w/w) ofcapsaicin, 0.03% (w/w) to about 0.05% (w/w) of capsaicin, 0.05% (w/w) toabout 0.07% (w/w) of capsaicin, 0.07% (w/w) to about 0.09% (w/w) ofcapsaicin, 0.09% (w/w) to about 0.11% (w/w) of capsaicin, or 0.11% (w/w)to about 0.13% (w/w) of capsaicin. In certain embodiments, theformulation comprises from about 0.04% (w/w) to about 0.06% (w/w) ofcapsaicin. In certain embodiments, the formulation comprises about 0.05%(w/w) of capsaicin. In certain embodiments, the formulation comprisesfrom about 0.08% (w/w) to about 0.12% (w/w) of capsaicin. In certainembodiments, the formulation comprises from about 0.12% (w/w) to about0.15% (w/w) of capsaicin, from about 0.15% (w/w) to about 0.18% (w/w) ofcapsaicin, from about 0.18% (w/w) to about 0.21% (w/w) of capsaicin,from about 0.21% (w/w) to about 0.25% (w/w) of capsaicin, or from about0.25% (w/w) to about 0.3% (w/w) of capsaicin. In certain embodiments,the formulation comprises about 0.1% (w/w) of capsaicin.

Additional Pain-Relief Agent

The formulation may optionally contain a further pain-relief agent. Forexample, in certain embodiments, the formulation may further comprise acaine alkaloid. Exemplary caine alkaloids include lidocaine, dibucaine,bupivacaine, ropivacaine, etidocaine, tetracaine, procaine, chlorocaine,prilocaine, mepivacaine, xylocaine, 2-chloroprocaine, andpharmaceutically acceptable salts thereof. In certain embodiments, theformulation further comprises lidocaine, such as where the lidocaine ispresent in an amount of about 0.5% (w/w), 1.0% (w/w), 2.0% (w/w), 3.0%(w/w) or 4.0% (w/w) of the formulation, or in an amount ranging fromabout 0.5% (w/w) to about 2.0% (w/w), or about 2.0% (w/w) to about 4.0%(w/w) of the formulation.

Sterility of the Formulation

The formulation may be further characterized according to the sterilityof the formulation and procedures used to sterilize the formulation.Accordingly, in certain embodiments, the formulation has a sterilityassurance level of from about 10¹ to 10⁻³, about 10⁻³ to about 10⁻⁴,about 10⁻⁴ to about 10⁻⁵, about 10⁻⁵ to about 10⁻⁶, or about 10⁻⁶ toabout 10⁻⁷, or a sterility assurance level that is more sterile than10⁻⁷. In certain embodiments, the sterility assurance level that is moresterile than about 10⁻³, about 10⁻⁴, about 10⁻⁵, or about 10⁻⁶.

One method for improving the sterility of the formulation is to pass theformulation through a sterile filter. Such filter may be a 0.2 micronsterilizing filter.

Alternatively, the formulation may be subjected to sterilization byheating to above ambient temperature. Accordingly, in certainembodiments, the formulation may be characterized by the feature thatthe formulation has been subjected to sterilization by heating to aboveambient temperature. In certain embodiments, the formulation may becharacterized by the feature that the formulation has been subjected tosterilization by heating to a temperature in the range of from about100° C. to about 135° C. In certain embodiments, the formulation hasbeen subjected to sterilization by heating to a temperature in the rangeof from about 120° C. to about 125° C. In certain embodiments, theformulation has been subjected to sterilization conditions that achievea F₀-value in the range of from about 6 to about 10. In certainembodiments, the formulation has been subjected to sterilizationconditions that achieve a F₀-value of about 8. In certain embodiments,the formulation has been subjected to sterilization conditions thatachieve a F₀-value in the range of from about 20 to about 30. In certainembodiments, the formulation has been subjected to sterilizationconditions that achieve a F₀-value of about 25.

Exemplary Formulations

In certain embodiments, the formulation is one of the formulations inTable 1 below.

TABLE 1 No. Formulation 1 An aqueous, capsaicin injectable formulation,comprising: a. about 0.03% (w/w) to about 0.3% (w/w) of capsaicin; b.about 0.1% (w/w) to about 3% (w/w) of a solubilizing agent, wherein thesolubilizing agent comprises (i) a polyethylene glycol ester of a(C₁₅-C₂₅) hydroxyalkanoic acid, (ii) a polyethylene glycol ester of a(C₁₅-C₂₅) hydroxyalkenoic acid, or (iii) a polyethylene glycol ester ofa (C₁₅-C₂₅) alkanoic acid substituted by a —OC(O)(C₁₄-C₂₄) hydroxyalkylgroup; c. about 0.001% (w/w) to about 2% (w/w) of an antioxidant; and d.at least 92% (w/w) water; and having a pH in the range of about 3 toabout 8. 2 An aqueous, capsaicin injectable formulation, comprising: a.about 0.04% (w/w) to about 0.06% (w/w) of capsaicin; b. about 0.7% (w/w)to about 1.3% (w/w) of a solubilizing agent, wherein the solubilizingagent comprises (i) a polyethylene glycol ester of a (C₁₅-C₂₅)hydroxyalkanoic acid, or (ii) a polyethylene glycol ester of a (C₁₅-C₂₅)hydroxyalkenoic acid; c. about 0.001% (w/w) to about 0.1% (w/w) of anantioxidant; and d. at least 92% (w/w) water; and having a pH in therange of about 4 to about 7. 3 An aqueous, capsaicin injectableformulation, comprising: a. about 0.04% (w/w) to about 0.06% (w/w) oftrans-capsaicin; b. about 0.7% (w/w) to about 1.3% (w/w) of asolubilizing agent, wherein the solubilizing agent comprises (a) fromabout 60% (w/w) to about 80% (w/w) of a mixture of(C₁₇)hydroxyalkyl-CO₂-(polyethylene glycolyl)-H and(C₁₇)hydroxyalkyl-CO₂—(C₁₇)alkylene-CO₂- (polyethylene glycolyl)-H, and(b) from about 20% (w/w) to about 40% (w/w) polyethylene glycol; c.about 0.001% (w/w) to about 0.1% (w/w) of an antioxidant; and d. atleast 95% (w/w) water; and having a pH in the range of about 4 to about7. 4 An aqueous, capsaicin injectable formulation, comprising: a. about0.08% (w/w) to about 0.12% (w/w) of capsaicin; b. about 1.8% (w/w) toabout 2.2% (w/w) of a solubilizing agent, wherein the solubilizing agentcomprises (i) a polyethylene glycol ester of a (C₁₅-C₂₅) hydroxyalkanoicacid, or (ii) a polyethylene glycol ester of a (C₁₅-C₂₅) hydroxyalkenoicacid; c. about 0.001% (w/w) to about 0.1% (w/w) of an antioxidant; andd. at least 93% (w/w) water; and having a pH in the range of about 4 toabout 7. 5 An aqueous, capsaicin injectable formulation, comprising: a.about 0.08% (w/w) to about 0.12% (w/w) of capsaicin; b. about 1.8% (w/w)to about 2.2% (w/w) of a solubilizing agent, wherein the solubilizingagent comprises (a) from about 60% (w/w) to about 80% (w/w) of a mixtureof (C₁₇)hydroxyalkyl-CO₂-(polyethylene glycolyl)-H and(C₁₇)hydroxyalkyl-CO₂—(C₁₇)alkylene-CO₂- (polyethylene glycolyl)-H, and(b) from about 20% (w/w) to about 40% (w/w) polyethylene glycol; c.about 0.001% (w/w) to about 0.1% (w/w) of an antioxidant; and d. atleast 93% (w/w) water; and having a pH in the range of about 4 to about7.

Exemplary more specific formulations are provided in Tables 2 and 3below.

TABLE 2 No. Formulation 1 An aqueous, capsaicin injectable formulation,comprising: a. about 0.04% (w/w) to about 0.06% (w/w) of capsaicin; b.about 0.5% (w/w) to about 1.5% (w/w) of a solubilizing agent, whereinthe solubilizing agent comprises

polyethylene glycol; c. about 0.005% (w/w) to about 0.015% (w/w) of anantioxidant; d. about 0.3% (w/w) to about 1% (w/w) of an alkali metalacetate; e. about 0.01% (w/w) to about 0.05% (w/w) of a chelating agent;f. about 0.3% (w/w) to about 0.9% (w/w) of a tonicity modifier; g. atleast 95% (w/w) water; and having a pH in the range of about 5 to about6. 2 An aqueous, capsaicin injectable formulation, comprising: a. about0.04% (w/w) to about 0.06% (w/w) of capsaicin; b. about 0.8% (w/w) toabout 1.2% (w/w) of a solubilizing agent, wherein the solubilizing agentcomprises

polyethylene glycol; c. about 0.005% (w/w) to about 0.015% (w/w) ofdibutylhydroxytoluene; d. about 0.3% (w/w) to about 1% (w/w) of sodiumacetate; e. about 0.01% (w/w) to about 0.05% (w/w) ofethylenediaminetetraacetic acid or a salt thereof; f. about 0.3% (w/w)to about 0.9% (w/w) of sodium chloride; g. at least 95% (w/w) water; andhaving a pH in the range of about 5 to about 6. 3 An aqueous, capsaicininjectable formulation, comprising: a. about 0.05% (w/w) oftrans-capsaicin; b. about 1% (w/w) of a solubilizing agent, wherein thesolubilizing agent comprises

polyethylene glycol; c. about 0.01% (w/w) dibutylhydroxytoluene; d.about 0.5% (w/w) to about 0.8% (w/w) of sodium acetate; e. about 0.01%(w/w) to about 0.05% (w/w) of ethylenediaminetetraacetic acid or a saltthereof; f. about 0.3% (w/w) to about 0.9% (w/w) of sodium chloride; g.at least 95% (w/w) water; and having a pH in the range of about 5 toabout 6. 4 An aqueous, capsaicin injectable formulation, comprising: a.about 0.08% (w/w) to about 0.12% (w/w) of capsaicin; b. about 1.5% (w/w)to about 2.5% (w/w) of a solubilizing agent, wherein the solubilizingagent comprises

polyethylene glycol; c. about 0.005% (w/w) to about 0.015% (w/w) of anantioxidant; d. about 0.1% (w/w) to about 1% (w/w) of an alkali metalcarboxylate compound; e. about 0.01% (w/w) to about 0.5% (w/w) of achelating agent; f. about 2% (w/w) to about 4% (w/w) of a tonicitymodifier; g. at least 93% (w/w) water; and having a pH in the range ofabout 5 to about 6. 5 An aqueous, capsaicin injectable formulation,comprising: a. about 0.08% (w/w) to about 0.12% (w/w) of capsaicin; b.about 1.8% (w/w) to about 2.2% (w/w) of a solubilizing agent, whereinthe solubilizing agent comprises

polyethylene glycol; c. about 0.005% (w/w) to about 0.015% (w/w) of anantioxidant; d. about 0.1% (w/w) to about 1% (w/w) of an alkali metalcarboxylate compound; e. about 0.01% (w/w) to about 0.5% (w/w) of achelating agent; f. about 2% (w/w) to about 4% (w/w) of a tonicitymodifier; g. at least 93% (w/w) water; and having a pH in the range ofabout 5 to about 6. 6 An aqueous, capsaicin injectable formulation,comprising: a. about 0.1% (w/w) of capsaicin; b. about 2% (w/w) of asolubilizing agent, wherein the solubilizing agent comprises

polyethylene glycol; c. about 0.005% (w/w) to about 0.015% (w/w) of anantioxidant; d. about 0.1% (w/w) to about 1% (w/w) of an alkali metalcarboxylate compound; e. about 0.01% (w/w) to about 0.5% (w/w) of achelating agent; f. about 2.5% (w/w) to about 3.5% (w/w) of a tonicitymodifier; g. at least 93% (w/w) water; and having a pH in the range ofabout 5 to about 6.

TABLE 3 No. Formulation 1 An aqueous, capsaicin injectable formulation,comprising: a. about 0.1% (w/w) of capsaicin; b. about 2% (w/w) of asolubilizing agent, wherein the solubilizing agent comprises

polyethylene glycol; c. about 0.01% (w/w) of an antioxidant; d. about0.1% (w/w) to about 1% (w/w) of an alkali metal citrate salt; e. about0.1% (w/w) of a chelating agent; f. about 3% (w/w) of a tonicitymodifier; and g. at least 93% (w/w) water. 2 An aqueous, capsaicininjectable formulation, comprising: a. about 0.1% (w/w) of capsaicin; b.about 2% (w/w) of a solubilizing agent, wherein the solubilizing agentcomprises

polyethylene glycol; c. about 0.01% (w/w) of dibutylhydroxytoluene; d.about 0.1% (w/w) to about 1% (w/w) of a disodium citrate salt; e. about0.1% (w/w) of ethylenediaminetetraacetic acid or a salt thereof f. about3% (w/w) of dextrose; g. at least 93% (w/w) water; and having a pH inthe range of about 5 to about 6. 3 An aqueous, capsaicin injectableformulation, comprising: a. about 0.1% (w/w) of trans-capsaicin; b.about 2% (w/w) of a solubilizing agent, wherein the solubilizing agentthat comprises

polyethylene glycol; c. about 0.01% (w/w) of dibutylhydroxytoluene; d.about 0.1% (w/w) to about 1% (w/w) of a disodium citrate salt; e. about0.1% (w/w) of ethylenediaminetetraacetic acid or a salt thereof; f.about 3% (w/w) of dextrose; g. at least 93% (w/w) water; and having a pHin the range of about 5 to about 6.

In yet other embodiments, the aqueous, capsaicin injectable formulationcomprises (a) about 0.04% (w/w) to about 0.06% (w/w) of capsaicin; (b)about 0.5% (w/w) to about 1.5% (w/w) of a solubilizing agent, whereinthe solubilizing agent comprises

and polyethylene glycol; (c) about 0.005% (w/w) to about 0.015% (w/w) ofan antioxidant; (d) about 0.2% (w/w) to about 1% (w/w) of an alkalimetal acetate; (e) about 0.01% (w/w) to about 0.05% (w/w) of a chelatingagent; (f) about 0.3% (w/w) to about 0.9% (w/w) of a tonicity modifier;and (g) at least 96% (w/w) water; and having a pH in the range of about5 to about 6.

In other embodiments, the aqueous, capsaicin injectable formulationcomprises (a) about 0.04% (w/w) to about 0.06% (w/w) of capsaicin; (b)about 0.8% (w/w) to about 1.2% (w/w) of a solubilizing agent, whereinthe solubilizing agent comprises

and polyethylene glycol; (c) about 0.005% (w/w) to about 0.015% (w/w) ofdibutylhydroxytoluene; (d) about 0.2% (w/w) to about 1% (w/w) of sodiumacetate; (e) about 0.01% (w/w) to about 0.05% (w/w) ofethylenediaminetetraacetic acid or a salt thereof; (f) about 0.3% (w/w)to about 0.9% (w/w) of sodium chloride; (g) at least 96% (w/w) water;and has a pH in the range of about 5 to about 6.

In other embodiments, the aqueous, capsaicin injectable formulationcomprises

-   -   a. about 0.04% (w/w) to about 0.06% (w/w) of capsaicin;    -   b. about 0.8% (w/w) to about 1.2% (w/w) of a solubilizing agent,        wherein the solubilizing agent comprises (a) about 70% (w/w) of        a mixture of

and (b) about 30% (w/w) polyethylene glycol;

-   -   c. about 0.005% (w/w) to about 0.015% (w/w) of        dibutylhydroxytoluene;    -   d. about 0.2% (w/w) to about 1% (w/w) of sodium acetate;    -   e. about 0.01% (w/w) to about 0.05% (w/w) of        ethylenediaminetetraacetic acid or a salt thereof;    -   f. about 0.3% (w/w) to about 0.9% (w/w) of sodium chloride;    -   g. at least 96% (w/w) water; and        -   having a pH in the range of about 5 to about 6.

In other embodiments, the aqueous, capsaicin injectable formulationcomprises

-   -   a. about 0.04% (w/w) to about 0.06% (w/w) of capsaicin;    -   b. about 0.8% (w/w) to about 1.2% (w/w) of a solubilizing agent,        wherein the solubilizing agent is a mixture of (a) about 70%        (w/w) of a mixture of

and (b) about 30% (w/w) polyethylene glycol;

-   -   c. about 0.005% (w/w) to about 0.015% (w/w) of        dibutylhydroxytoluene;    -   d. about 0.2% (w/w) to about 1% (w/w) of sodium acetate;    -   e. about 0.01% (w/w) to about 0.05% (w/w) of        ethylenediaminetetraacetic acid or a salt thereof;    -   f. about 0.3% (w/w) to about 0.9% (w/w) of sodium chloride;    -   g. at least 96% (w/w) water; and        -   having a pH in the range of about 5 to about 6.

In other embodiments, the aqueous, capsaicin injectable formulationcomprises

-   -   a. about 0.05% (w/w) of capsaicin;    -   b. about 1% (w/w) of a solubilizing agent, wherein the        solubilizing agent comprises

and polyethylene glycol;

-   -   c. about 0.005% (w/w) to about 0.015% (w/w) of        dibutylhydroxytoluene;    -   d. about 0.2% (w/w) to about 1% (w/w) of sodium acetate;    -   e. about 0.01% (w/w) to about 0.05% (w/w) of        ethylenediaminetetraacetic acid or a salt thereof;    -   f. about 0.3% (w/w) to about 0.9% (w/w) of sodium chloride;    -   g. at least 96% (w/w) water; and        -   having a pH of about 5.5.

In other embodiments, the aqueous, capsaicin injectable formulationcomprises

-   -   a. about 0.05% (w/w) of capsaicin;    -   b. about 1% (w/w) of a solubilizing agent, wherein the        solubilizing agent is a mixture of

and polyethylene glycol;

-   -   c. about 0.005% (w/w) to about 0.015% (w/w) of        dibutylhydroxytoluene;    -   d. about 0.2% (w/w) to about 1% (w/w) of sodium acetate;    -   e. about 0.01% (w/w) to about 0.05% (w/w) of        ethylenediaminetetraacetic acid or a salt thereof;    -   f. about 0.3% (w/w) to about 0.9% (w/w) of sodium chloride;    -   g. at least 96% (w/w) water; and        -   having a pH of about 5.5.

Each of the foregoing formulations may be further characterizedaccording to the weight-average molecular weight of the polyethyleneglycol component(s). Accordingly, in certain embodiments, thepolyethylene glycol has a weight-average molecular weight in the rangeof about 200 g/mol to about 1500 g/mol. In certain embodiments, thepolyethylene glycol has a weight-average molecular weight in the rangeof about 200 g/mol to about 1000 g/mol. In certain embodiments, thepolyethylene glycol has a weight-average molecular weight in the rangeof about 300 g/mol to about 900 g/mol. In certain embodiments, thepolyethylene glycol has a weight-average molecular weight in the rangeof about 500 g/mol to about 800 g/mol. In certain embodiments, thepolyethylene glycol has a weight-average molecular weight in the rangeof about 600 g/mol to about 700 g/mol. In certain embodiments, thepolyethylene glycol has a weight-average molecular weight in the rangeof about 100 g/mol to about 300 g/mol, about 300 g/mol to about 500g/mol, about 500 g/mol to about 1000 g/mol, about 1000 g/mol to about1500 g/mol, about 1500 g/mol to about 2000 g/mol, or about 2000 g/mol toabout 2500 g/mol.

Additionally, each of the foregoing formulations may be furthercharacterized according to the weight-average molecular weight of anypolyethylene glycolyl component. For example, in certain embodiments,the polyethylene glycolyl has a weight-average molecular weight in therange of about 100 g/mol to about 3000 g/mol. In certain embodiments,the polyethylene glycolyl has a weight-average molecular weight in therange of about 200 g/mol to about 1500 g/mol. In certain embodiments,the polyethylene glycolyl has a weight-average molecular weight in therange of about 200 g/mol to about 1000 g/mol. In certain embodiments,the polyethylene glycolyl has a weight-average molecular weight in therange of about 300 g/mol to about 900 g/mol. In certain embodiments, thepolyethylene glycolyl has a weight-average molecular weight in the rangeof about 500 g/mol to about 800 g/mol. In certain embodiments, thepolyethylene glycolyl has a weight-average molecular weight in the rangeof about 600 g/mol to about 750 g/mol. In certain embodiments, thepolyethylene glycolyl has a weight-average molecular weight in the rangeof about 600 g/mol to about 700 g/mol. In certain embodiments, thepolyethylene glycolyl has a weight-average molecular weight of about 660g/mol. In certain embodiments, the polyethylene glycolyl has aweight-average molecular weight in the range of about 100 g/mol to about300 g/mol, about 300 g/mol to about 500 g/mol, about 500 g/mol to about1000 g/mol, about 1000 g/mol to about 1500 g/mol, about 1500 g/mol toabout 2000 g/mol, or about 2000 g/mol to about 2500 g/mol.

In yet other embodiments, the aqueous, capsaicin injectable formulationcomprises (a) about 0.04% (w/w) to about 0.06% (w/w) of capsaicin; (b)about 0.5% (w/w) to about 1.5% (w/w) of a solubilizing agent, whereinthe solubilizing agent comprises macrogol 15 hydroxystearate; (c) about0.005% (w/w) to about 0.015% (w/w) of an antioxidant; (d) about 0.2%(w/w) to about 1% (w/w) of an alkali metal acetate; (e) about 0.01%(w/w) to about 0.05% (w/w) of a chelating agent; (f) about 0.3% (w/w) toabout 0.9% (w/w) of a tonicity modifier; and (g) at least 96% (w/w)water; and having a pH in the range of about 5 to about 6. In otherembodiments, the aqueous, capsaicin injectable formulation comprises (a)about 0.04% (w/w) to about 0.06% (w/w) of capsaicin; (b) about 0.8%(w/w) to about 1.2% (w/w) of a solubilizing agent, wherein thesolubilizing agent comprises macrogol 15 hydroxystearate; (c) about0.005% (w/w) to about 0.015% (w/w) of dibutylhydroxytoluene; (d) about0.2% (w/w) to about 1% (w/w) of sodium acetate; (e) about 0.01% (w/w) toabout 0.05% (w/w) of ethylenediaminetetraacetic acid or a salt thereof;(f) about 0.3% (w/w) to about 0.9% (w/w) of sodium chloride; (g) atleast 96% (w/w) water; and has a pH in the range of about 5 to about 6;wherein the formulation has been subjected to sterilization procedures(e.g., sterilization by heating to above ambient temperature (e.g.,autoclave sterilization)). In other embodiments, the aqueous, capsaicininjectable formulation comprises (a) about 0.05% (w/w) of capsaicin; (b)about 1% (w/w) of a solubilizing agent, wherein the solubilizing agentcomprises macrogol 15 hydroxystearate; (c) about 0.005% (w/w) to about0.015% (w/w) of dibutylhydroxytoluene; (d) about 0.2% (w/w) to about 1%(w/w) of sodium acetate; (e) about 0.01% (w/w) to about 0.05% (w/w) ofethylenediaminetetraacetic acid or a salt thereof; (f) about 0.3% (w/w)to about 0.9% (w/w) of sodium chloride; (g) at least 96% (w/w) water;and having a pH of about 5.5; wherein optionally the formulation hasbeen subjected to sterilization procedures (e.g., sterilization byheating to above ambient temperature (e.g., autoclave sterilization)).

Exemplary more specific formulations are provided in Tables 4 and 5below.

TABLE 4 No. Formulation 1 An aqueous, capsaicin injectable formulation,comprising: a. about 0.05% (w/w) of trans-capsaicin; b. about 1% (w/w)of a solubilizing agent, wherein the solubilizing agent is a mixture of

polyethylene glycol; wherein the polyethylene glycolyl has a weightaverage molecular weight of about 660 g/mol; c. about 0.01% (w/w)dibutylhydroxytoluene; d. about 0.68% (w/w) of sodium acetate or amixture of sodium acetate and acetic acid; e. about 0.025% (w/w) ofethylenediaminetetraacetic acid or a salt thereof; f. about 0.6% (w/w)of sodium chloride; g. at least 97% (w/w) water; and having a pH ofabout 5.5. 2 An aqueous, capsaicin injectable formulation, comprising:a. 0.05% (w/w) of trans-capsaicin; b. 1% (w/w) of a solubilizing agent,wherein the solubilizing agent is a mixture of

polyethylene glycol; wherein the polyethylene glycolyl has a weightaverage molecular weight of about 660 g/mol; c. 0.01% (w/w)dibutylhydroxytoluene; d. 0.68% (w/w) of sodium acetate or a mixture ofsodium acetate and acetic acid; e. 0.025% (w/w) ofethylenediaminetetraacetic acid or a salt thereof; f. 0.6% (w/w) ofsodium chloride; g. at least 97% (w/w) water; and having a pH of 5.5. 3An aqueous, capsaicin injectable formulation, comprising: a. about 0.05%(w/w) of trans-capsaicin; b. about 1% (w/w) of a solubilizing agent,wherein the solubilizing agent is a mixture of

polyethylene glycol; wherein the polyethylene glycolyl has a weightaverage molecular weight of about 660 g/mol; c. about 0.01% (w/w)dibutylhydroxytoluene; d. about 0.34% (w/w) of sodium acetate or amixture of sodium acetate and acetic acid; e. about 0.025% (w/w) ofethylenediaminetetraacetic acid or a salt thereof; f. about 0.75% (w/w)of sodium chloride; g. at least 97% (w/w) water; and having a pH ofabout 5.5. 4 An aqueous, capsaicin injectable formulation, comprising:a. 0.05% (w/w) of trans-capsaicin; b. 1% (w/w) of a solubilizing agent,wherein the solubilizing agent is a mixture of

polyethylene glycol; wherein the polyethylene glycolyl has a weightaverage molecular weight of about 660 g/mol; c. 0.01% (w/w)dibutylhydroxytoluene; d. 0.34% (w/w) of sodium acetate or a mixture ofsodium acetate and acetic acid; e. 0.025% (w/w) ofethylenediaminetetraacetic acid or a salt thereof; f. 0.75% (w/w) ofsodium chloride; g. at least 97% (w/w) water; and having a pH of 5.5.

TABLE 5 No. Formulation 1 An aqueous, capsaicin injectable formulation,comprising: a. about 0.05% (w/w) of trans-capsaicin; b. about 1% (w/w)of a solubilizing agent, wherein the solubilizing agent is a mixture of

polyethylene glycol; wherein the polyethylene glycolyl has a weightaverage molecular weight of about 660 g/mol; c. about 0.01% (w/w)dibutylhydroxytoluene; d. about 0.22% (w/w) of sodium citrate or amixture of sodium citrate and citric acid; e. about 0.025% (w/w) ofethylenediaminetetraacetic acid or a salt thereof; f. about 0.8% (w/w)of sodium chloride; g. at least 97% (w/w) water; and having a pH ofabout 5.5. 2 An aqueous, capsaicin injectable formulation, comprising:a. 0.05% (w/w) of trans-capsaicin; b. 1% (w/w) of a solubilizing agent,wherein the solubilizing agent is a mixture of

polyethylene glycol; wherein the polyethylene glycolyl has a weightaverage molecular weight of about 660 g/mol; c. 0.01% (w/w)dibutylhydroxytoluene; d. 0.22% (w/w) of sodium citrate or a mixture ofsodium citrate and citric acid; e. 0.025% (w/w) ofethylenediaminetetraacetic acid or a salt thereof; f. 0.8% (w/w) ofsodium chloride; g. at least 97% (w/w) water; and having a pH of 5.5. 3An aqueous, capsaicin injectable formulation, comprising: a. about 1%(w/w) of trans-capsaicin; b. about 2% (w/w) of a solubilizing agent,wherein the solubilizing agent is a mixture of

polyethylene glycol; wherein the polyethylene glycolyl has a weightaverage molecular weight of about 660 g/mol; c. about 0.01% (w/w)dibutylhydroxytoluene; d. about 20 mM of sodium citrate or a mixture ofsodium citrate and citric acid; e. about 0.1% (w/w) ofethylenediaminetetraacetic acid or a salt thereof; f. about 3.15% (w/w)of dextrose; g. at least 93% (w/w) water; and having a pH of about 5 toabout 6. 4 An aqueous, capsaicin injectable formulation, comprising: a.1% (w/w) of trans-capsaicin; b. 2% (w/w) of a solubilizing agent,wherein the solubilizing agent is a mixture of

polyethylene glycol; wherein the polyethylene glycolyl has a weightaverage molecular weight of about 660 g/mol; c. 0.01% (w/w)dibutylhydroxytoluene; d. 20 mM of sodium citrate or a mixture of sodiumcitrate and citric acid; e. 0.1% (w/w) of ethylenediaminetetraaceticacid or a salt thereof; f. 3.15% (w/w) of dextrose; g. at least 93%(w/w) water; and having a pH of about 5 to about 6.

In certain embodiments, the formulation is one of the formulationsdescribed in Tables 1-5 above, wherein the formulation has an osmolalityin the range of from about 240 mOsm/kg to about 340 mOsm/kg. In certainembodiments, the formulation is one of the formulations described inTables 1-5 above, wherein the formulation has an osmolality in the rangefrom about 270 mOsm/kg to about 330 mOsm/kg.

Stability of the Aqueous Capsaicin Injectable Formulations

A formulation containing capsaicin can be further characterizedaccording to the stability of the formulation upon storage. For example,in certain embodiments, the formulation is characterized by the featurethat less than 1% of the capsaicin degrades upon storage at 25° C. for24 weeks. In certain other embodiments, less than 0.5% of the capsaicindegrades upon storage at 25° C. for 24 weeks. In certain otherembodiments, less than 0.1% of the capsaicin degrades upon storage at25° C. for 24 weeks. In certain other embodiments, less than 1% of thecapsaicin degrades upon storage at 40° C. for 24 weeks. In certain otherembodiments, less than 0.5% of the capsaicin degrades upon storage at40° C. for 24 weeks.

Amount of Capsaicin-dimer in an Aqueous Capsaicin Injectable Formulation

A formulation containing capsaicin can be further characterizedaccording to the amount of any impurities in the formulation, such asthe amount of capsaicin-dimer having the following formula:

Accordingly, in certain embodiments, the formulation is characterized bythe feature that it contains less than 3% (w/w) of capsaicin-dimerhaving the following structure:

In certain other embodiments, the formulation contains less than 2%(w/w) of the capsaicin-dimer. In certain other embodiments, theformulation contains less than 1% (w/w) of the capsaicin-dimer. Incertain other embodiments, the formulation contains less than 0.6% (w/w)of the capsaicin-dimer.

In certain other embodiments, upon storage at 25° C. for 12 weeks, theformulation contains less than 3% (w/w) of capsaicin-dimer having thefollowing structure:

In certain other embodiments, upon storage at 25° C. for 12 weeks, theformulation contains less than 2% (w/w) of capsaicin-dimer. In certainother embodiments, upon storage at 25° C. for 24 weeks, the formulationcontains less than 1% (w/w) of the capsaicin-dimer. In certain otherembodiments, upon storage at 25° C. for 24 weeks, the formulationcontains less than 0.6% (w/w) of the capsaicin-dimer.Amount of Substituted 1,1′-Biphenyl Compound in an Aqueous CapsaicinInjectable Formulation

A formulation containing capsaicin can be further characterizedaccording to the amount of substituted 1,1′-biphenyl compound having thefollowing structure:

In certain embodiments, the formulation contains less than 2% (w/w) ofthe substituted 1,1′-biphenyl compound. In certain embodiments, theformulation contains less than 1% (w/w) of the substituted 1,1′-biphenylcompound.

In certain other embodiments, upon storage at 25° C. for 12 weeks, theformulation contains less than 3% (w/w) of the aforementionedsubstituted 1,1′-biphenyl compound. In certain other embodiments, uponstorage at 25° C. for 12 weeks, the formulation contains less than 2%(w/w) of the substituted 1,1′-biphenyl compound. In certain otherembodiments, upon storage at 25° C. for 24 weeks, the formulationcontains less than 1% (w/w) of the substituted 1,1′-biphenyl compound.In certain other embodiments, upon storage at 25° C. for 24 weeks, theformulation contains less than 0.6% (w/w) of substituted 1,1′-biphenylcompound.

Amount of Substituted 1,1′-Bibenzyl Compound in an Aqueous CapsaicinInjectable Formulation

A formulation containing capsaicin can be further characterizedaccording to the amount of substituted 1,1′-bibenzyl compound having thefollowing structure:

In certain embodiments, the formulation contains less than 2% (w/w) ofthe substituted 1,1′-bibenzyl compound. In certain embodiments, theformulation contains less than 1% (w/w) of the substituted 1,1′-bibenzylcompound. In certain embodiments, the formulation contains less than0.5% (w/w) of the substituted 1,1′-bibenzyl compound. In certainembodiments, the formulation contains less than 0.1% (w/w) of thesubstituted 1,1′-bibenzyl compound. In certain embodiments, theformulation contains less than 0.05% (w/w) of the substituted1,1′-bibenzyl compound.

In certain other embodiments, upon storage at 25° C. for 12 weeks, theformulation contains less than 2% (w/w) of the aforementionedsubstituted 1,1′-bibenzyl compound. In certain other embodiments, uponstorage at 25° C. for 12 weeks, the formulation contains less than 1%(w/w) of the substituted 1,1′-bibenzyl compound. In certain otherembodiments, upon storage at 25° C. for 24 weeks, the formulationcontains less than 0.5% (w/w) of the substituted 1,1′-bibenzyl compound.In certain other embodiments, upon storage at 25° C. for 24 weeks, theformulation contains less than 0.1% (w/w) of substituted 1,1′-bibenzylcompound.

Amount of Substituted 1,2′-Bibenzyl Compound in an Aqueous CapsaicinInjectable Formulation

A formulation containing capsaicin can be further characterizedaccording to the amount of substituted 1,2′-bibenzyl compound having thefollowing structure:

In certain embodiments, the formulation contains less than 2% (w/w) ofthe substituted 1,2′-bibenzyl compound. In certain embodiments, theformulation contains less than 1% (w/w) of the substituted 1,2′-bibenzylcompound. In certain embodiments, the formulation contains less than0.5% (w/w) of the substituted 1,2′-bibenzyl compound. In certainembodiments, the formulation contains less than 0.1% (w/w) of thesubstituted 1,2′-bibenzyl compound. In certain embodiments, theformulation contains less than 0.05% (w/w) of the substituted1,1′-bibenzyl compound.

In certain other embodiments, upon storage at 25° C. for 12 weeks, theformulation contains less than 2% (w/w) of the aforementionedsubstituted 1,2′-bibenzyl compound. In certain other embodiments, uponstorage at 25° C. for 12 weeks, the formulation contains less than 1%(w/w) of the substituted 1,2′-bibenzyl compound. In certain otherembodiments, upon storage at 25° C. for 24 weeks, the formulationcontains less than 0.5% (w/w) of the substituted 1,2′-bibenzyl compound.In certain other embodiments, upon storage at 25° C. for 24 weeks, theformulation contains less than 0.1% (w/w) of substituted 1,2′-bibenzylcompound.

Amount of 5-Oxo-Capsaicin in an Aqueous Capsaicin Injectable Formulation

A formulation containing capsaicin can be further characterizedaccording to the amount of 5-oxo-capsaicin having the followingstructure:

In certain embodiments, the formulation contains less than 2% (w/w) of5-oxo-capsaicin. In certain embodiments, the formulation contains lessthan 1% (w/w) of 5-oxo-capsaicin. In certain embodiments, theformulation contains less than 0.5% (w/w) of 5-oxo-capsaicin. In certainembodiments, the formulation contains less than 0.1% (w/w) of5-oxo-capsaicin. In certain embodiments, the formulation contains lessthan 0.05% (w/w) of 5-oxo-capsaicin.

In certain other embodiments, upon storage at 25° C. for 12 weeks, theformulation contains less than 2% (w/w) of 5-oxo-capsaicin. In certainother embodiments, upon storage at 25° C. for 12 weeks, the formulationcontains less than 1% (w/w) of 5-oxo-capsaicin. In certain otherembodiments, upon storage at 25° C. for 24 weeks, the formulationcontains less than 0.5% (w/w) of 5-oxo-capsaicin. In certain otherembodiments, upon storage at 25° C. for 24 weeks, the formulationcontains less than 0.1% (w/w) of 5-oxo-capsaicin.

Amount of Particulate Matter in an Aqueous Capsaicin InjectableFormulation

Formulations herein can be further characterized according to the amountof particulate matter present in the formulation. Accordingly, incertain embodiments, a 2 mL aliquot of the formulation contains lessthan 6000 particles having an average diameter of ≥10 μm. In certainembodiments, a 2 mL aliquot of the formulation contains less than 3000,2000, 1000, 750, 500, 400, 300, 200, or 100 particles having an averagediameter of ≥10 μm. In certain embodiments, a 2 mL aliquot of theformulation contains less than 1500 particles having an average diameterof ≥10 μm. In certain embodiments, a 2 mL aliquot of the formulationcontains less than 1000 particles having an average diameter of ≥10 μm.

Further, in certain embodiments, a 2 mL aliquot of the formulationcontains less than 1000 particles having an average diameter of ≥25 μm.In certain embodiments, a 2 mL aliquot of the formulation contains lessthan 750, 700, 600, 500, 400, 300, 200, 100, 75, 50, 40, 30, 25, 20, 15,or 10 particles having an average diameter of ≥25 μm. In certainembodiments, a 2 mL aliquot of the formulation contains less than 600particles having an average diameter of ≥25 μm. In certain embodiments,a 2 mL aliquot of the formulation contains less than 15 particles havingan average diameter of ≥25 μm.

Further, in certain embodiments, a 2 mL aliquot of the formulation thathas been stored at 25° C. and 60% Relative Humidity for a duration of 3months contains less than 6000 particles having an average diameter of≥10 μm. In certain embodiments, a 2 mL aliquot of the formulation thathas been stored at 25° C. and 60% Relative Humidity for a duration of 3months contains less than 3000, 2000, 1000, 750, 500, 400, 300, 200, or100 particles having an average diameter of ≥10 μm. In certainembodiments, a 2 mL aliquot of the formulation that has been stored at25° C. and 60% Relative Humidity for a duration of 3 months containsless than 1500 particles having an average diameter of ≥10 μm. Incertain embodiments, a 2 mL aliquot of the formulation that has beenstored at 25° C. and 60% Relative Humidity for a duration of 3 monthscontains less than 1000 particles having an average diameter of ≥10 μm.

Further, in certain embodiments, a 2 mL aliquot of the formulation thathas been stored at 25° C. and 60% Relative Humidity for a duration of 3months contains less than 1000 particles having an average diameter of≥25 μm. In certain embodiments, a 2 mL aliquot of the formulation thathas been stored at 25° C. and 60% Relative Humidity for a duration of 3months contains less than 750, 700, 600, 500, 400, 300, 200, 100, 75,50, 40, 30, 25, 20, 15, or 10 particles having an average diameter of≥25 μm. In certain embodiments, a 2 mL aliquot of the formulation thathas been stored at 25° C. and 60% Relative Humidity for a duration of 3months contains less than 600 particles having an average diameter of≥25 μm. In certain embodiments, a 2 mL aliquot of the formulation thathas been stored at 25° C. and 60% Relative Humidity for a duration of 3months contains less than 15 particles having an average diameter of ≥25μm.

Amount of Optional Other Components in the Injectable Formulations

Formulations herein can be further characterized according to the amountof optional other components. For example, in certain embodiments, theformulation contains less than 0.1% (w/w) of any polysorbate (e.g.,polysorable 20 or polysorbate 80). In certain embodiments, theformulation does not contain any polysorbate. In certain embodiments,the formulation contains less than 0.1% (w/w) of any polysorbate,cyclodextrin, or alcohol. In certain embodiments, the formulation doesnot contain any polysorbate, cyclodextrin, or alcohol.

In yet other embodiments, other than said solubilizing agent, theformulation contains less than 0.1% (w/w) of any polymer,oligomer-containing agent, or agent that improves the solubility ofcapsaicin. In yet other embodiments, other than said solubilizing agent,the formulation does not contain any polymer, oligomer-containing agent,or agent that improves the solubility of capsaicin. In yet otherembodiments, the formulation contains less than 0.1% (w/w) of anycyclodextrin, cellulose, alcohol (e.g., menthol), or hyaluronic acid. Inyet other embodiments, the formulation does not contain anycyclodextrin, cellulose, alcohol (e.g., menthol), or hyaluronic acid.

In certain embodiments, the formulation contains less than 0.1% (w/w) ofany phospholipid, polysaccharide, protein polymer, cellulose, sorbitanester, or histidine. In certain embodiments, the formulation does notcontain of any phospholipid, polysaccharide, protein polymer, cellulose,sorbitan ester, or histidine. In certain embodiments, the formulationcontains less than 0.1% (w/w) of any polyvinylpyrrolidone polymer. Incertain embodiments, the formulation does not contain anypolyvinylpyrrolidone polymer.

In certain embodiments, the formulation contains less than 0.5% (w/w) ofany polyalkylene glycol (e.g., polyethylene glycol) polymer. In certainembodiments, the formulation contains less than 0.3% (w/w), 0.25% (w/w),0.2% (w/w), 0.15% (w/w), 0.1% (w/w), 0.05% (w/w) 0.01% (w/w) of anypolyalkylene glycol (e.g., polyethylene glycol) polymer.

In certain embodiments, the formulation contains less than 0.5% (w/w) ofany surfactant. In certain embodiments, the formulation contains lessthan 0.3% (w/w), 0.25% (w/w), 0.2% (w/w), 0.15% (w/w), 0.1% (w/w), 0.05%(w/w) 0.01% (w/w) of any surfactant. In certain embodiments, but for anycomponent of the formulation named in the description of the formulationthat would qualify as a surfactant, the formulation does not contain anyother agent that is a surfactant.

III. Unit Dosage Forms

The invention provides a unit dosage form comprising a formulationdescribed herein, such as in any one of Tables 1-5. The unit dosage formcan be characterized by, for example, the volume of the unit dosageform, such as where the unit dosage form has a volume in the range ofabout 0.5 mL to about 3 mL. In certain embodiments, the unit dosage formhas a volume in the range of about 1.8 mL to about 2.2 mL. In certainother embodiments, the unit dosage form has a volume of about 2 mL.

In certain embodiments, the unit dosage form is characterized by thefeature that the formulation is sealed in a container containing aninert gas (such as nitrogen gas).

In certain embodiments, the unit dosage form is characterized by theidentity of the container housing the unit dosage form, such as wherethe unit dosage form is in a syringe.

IV. Therapeutic Applications

The invention provides a method of treating pain in a patient. Themethod comprises administering to a patient in need thereof atherapeutically effective amount of a formulation described herein, suchas a formulation in any one of Tables 1-5, to a site at or near thelocation of pain, in order to treat the pain.

The invention provides a method of treating pain in a patient, whereinthe method comprises administering to a patient in need thereof atherapeutically effective amount of a formulation described herein, suchas a formulation in any one of Tables 1-5, in order to treat the pain.

Another aspect of the invention provides for the use of a formulationdescribed herein (such as a formulation in any one of Tables 1-5) in themanufacture of a medicament. The medicament may be for treating pain ina patient.

Types of Pain

Various types of pain are contemplated to be treated using formulationsdescribed herein. Exemplary types of pain for treatment include pain dueto nerve injury (e.g., a neuroma or a neuroma in continuity), pain dueto a tumor (e.g., a tumor in soft tissue), pain associated with apainful trigger point, pain due to inflammation, and pain due to injuryto tissue. In certain embodiments, the pain is due to a neuropathy,tumor, or inflammation. In other embodiments, the pain is due toinflammation of soft tissue. In other embodiments, the pain is due toinflammation of a joint, tendon, nerve, or muscle. In other embodiments,the pain is associated with a painful trigger point or tissue injury. Inother embodiments, the pain is visceral pain. In yet other embodiments,the pain is due to a metabolic disease (e.g., diabetes, hemochromatosis,or Wilson's Disease), a hematologic disease (e.g., sickle cell disease),a coagulopathy (e.g., hemophilia AB or factor VII deficiency), anabnormal deposition of substances into tissues (e.g., amyloid orlipodystrophy). In yet other embodiments, the pain is due to a change inlocal tissue structure, such as scarring, abnormal healing, lack ofhealing, or pressure in or on tissue.

More specific description of types of pain for treatment are providedbelow.

In certain embodiments, the pain is due to tendonitis, a myalgia (i.e.,pain originating from disease and/or inflammation of muscle), bone orjoint pain associated with inflammation, bone or joint pain due to aninjury, or bone or joint pain due to arthritis associated with adegenerative disease, rheumatoid arthritis, osteoarthritis, or otherarthritic condition. In yet other embodiments, the pain is due tobursitis, a sprain, a fracture, surgery, ligament inflammation, orligament damage.

In certain embodiments, the pain is due to a tumor. The pain due to atumor may be pain due to a metastatic tumor. In certain embodiments, thetumor may occur in the breast, kidney, brain, colon, colorectal tissue,prostate, cervix, uterus, lung, or bone. In certain other embodiments,the tumor may occur in the breast, kidney, brain, colon, colorectaltissue, prostate, cervix, uterus, or lung. In yet other embodiments, thetumor may occur in the skin, muscle, ovary, stomach, a blood vessel,cartilage, sinus, esophagus, eye, pancreas, liver, gall bladder, testes,lymph node, bladder, or a nerve. In yet other embodiments, the pain isdue to a liquid tumor. The tumor may be further characterized by, forexample, whether it is malignant or benign.

In certain embodiments, the pain to be treated is visceral pain. Incertain other embodiments, the pain to be treated is nociceptive pain(i.e., pain transmitted across intact neuronal pathways), neuropathicpain (i.e., pain caused by damage to neural structures), pain from nerveinjury (i.e., a neuroma or neuroma in continuity), pain from a neuralgia(i.e., pain originating from disease and/or inflammation of nerves),pain associated with a neurotransmitter-dysregulation syndrome (i.e., adisruption in quantity/quality of neurotransmitter molecules associatedwith signal transmission in normal nerves), or pain associated with anorthopedic disorder such as a condition of the foot, knee, hip, spine,shoulder, elbow, hand, head, or neck. In yet other embodiments, the painto be treated is pain from a therapeutic intervention (e.g.,chemotherapy, radiation, a toxin) or pain associated with tissuedeposition of a material (e.g., an amyloid, a lipodystrophy, or crystaldeposition disease).

Exemplary types of nociceptive pain include, for example, post-operativepain, a cluster headache, dental pain, surgical pain, pain resultingfrom a severe burn, post-partum pain, angina, genito-urinary tract pain,pain associated with a sports injury (e.g., tendonitis or bursitis),pain due to joint degeneration, and pain due to prostatitis or cystitis.In certain embodiments, the pain is bladder pain. Additional types ofnociceptive pain include, for example, chronic headache (e.g., clusterheadache), pain from scarring in any location, pain associated with atraumatic injury, pain due to prostatitis, gall bladder pain, and paindue to one or more of the following: a strain, sprain, fracture,dislocation, myalgia, or tissue damage.

Exemplary neuropathies include, for example, syndromes of acuteascending motor paralysis with variable disturbance of sensory function;syndromes of subacute sensorimotor paralysis; syndromes of acquiredforms of chronic sensorimotor polyneuropathy; syndromes of determinedforms of genetic chronic polyneuropathy; syndromes of recurrent orrelapsing polyneuropathy; and syndromes of mononeuropathy or multipleneuropathies. Exemplary syndromes of acute ascending motor paralysisinclude acute idiopathic polyneuritis, Landry-Guillain-Barre Syndrome,acute immune-mediated polyneuritis, infectious mononucleosispolyneuritis, hepatitis polyneuritis, diptheric polyneuropathy,porphyric polyneuropathy, toxic polyneuropathy (e.g., thallium), acuteaxonal polyneuropathy, acute panautonomic neuropathy, vaccinogenic,serogenic, paraneoplastic, metabolic, toxic, chemotherapeutic,radiation, an infiltrative neuropathy, and polyarteretic and lupuspolyneuropathy.

Exemplary syndromes of subacute sensorimotor paralysis includedeficiency states (e.g., beriberi, pellagra, and vitamin B12); heavymetal/industrial solvent poisonings (e.g., arsenic or lead); drug use oroverdose (e.g., isoniazid, disulfuram, platinum-based chemotherapy(e.g., cisplatin), vincristine, taxol, or chloramphenicol overdose);uremic polyneuropathy; metabolic (e.g., diabetes); infiltrative (e.g.,amyloid, crystal, metal, or lipodystrophies); sarcoidosis; ischemicneuropathy and peripheral vascular disease; AIDS; and radiation(radiotherapy).

Exemplary syndromes of chronic sensorimotor include a carcinoma, myelomaand other malignancies; paraproteinemias; uremia; beriberi (usuallysubacute), diabetes, hypo/hyperthyroidism; rheumatic and connectivetissue disease; amyloidosis; leprosy; Lyme disease, and sepsis.

Exemplary genetic chronic polyneuropathies include dominant mutilatingsensory neuropathy (adult); recessive mutilating sensory neuropathy(childhood); congenital insensitivity to pain; spinocerebellardegenerations; Riley Day Syndrome; Universal Anesthesia Syndrome;polyneuropathies with metabolic disorder; and mixedsensorimotor-autonomic type polyneuropathies.

Exemplary recurrent/relapsing polyneuropathies include idiopathicpolyneuritis; porphyria; chronic inflammatory polyradiculoneuropathy;mononeuritis multiplex; beriberi/drug overdose; refsum disease andtangier disease.

Exemplary mono/multiple neuropathies include pressure palsies; traumaticneuropathies (e.g., irradiation or electrical injury); serum;vaccinogenic (e.g., rabies, smallpox); herpes zoster; neoplasticinfiltration; leprosy; diptheretic wound infections; migrant sensoryneuropathy; shingles; and post-herpetic neuralgia.

Neurotransmitter-dysregulation pain syndromes include, for example,generalized syndromes, localized syndromes, craniofascial pain, vasculardisease, rectal pain, perineum pain, external genitalia pain, chronicregional pain syndrome, and local syndromes of the leg/foot.

Exemplary generalized syndromes include stump pain, causalgia, reflexsympathetic dystrophy, fibromyalgia or local and/or diffuse myofascialpain and burns. Exemplary localized syndromes include trigeminalneuralgia; acute herpes zoster; panautonomic neuralgia; geniculateneuralgia (Romsay Hunt Syndrome); glossopharyngeal neuralgia; vagusnerve neuralgia and occipital neuralgia. Craniofacial pain includestemporomandibular pain. Suboccipital and cervical musculoskeletaldisorders include myofascial syndrome, which includes cervical, spraincervical hyperextension (whiplash); sternocleidomastoid muscle;trapezius muscle; and stylohyoid process syndrome (Eagle's syndrome).Vascular disease includes Raynaud's disease; Raynaud's phenomenon;frostbite; erythema pernio (chilblains); acrocyanosis and livedoreticularis. Rectal, perineum and external genitalia pain includeiliohypogastric neuralgia; iliolinguinal nerve; genotifemoral nerve andtesticular pain. Local syndromes of the leg/foot include lateralcutaneous neuropathy (neuralgia paresthetica); obturator neuralgia;femoral neuralgia; sciatica neuralgia; interdigital neuralgia of thefoot (Morton's metatarsalgia or neuroma); injection neuropathy andpainful legs and moving toes.

In certain embodiments, the pain is due to chronic post-herniorrhaphy,Morton's neuroma, a mastectomy, a median sternotomy, an orthopedicdisorder, bursitis, tendonitis, ligamentous injury, meniscal injury,back/neck pain, a heel spur, or open or laparoscopic cholecystectomy.

Exemplary orthopedic disorders that may cause pain contemplated fortreatment using formulations described herein include, for example,disorders of the knee, shoulders, back, hip, spine, elbows, foot, handand other disorders, which involve pain at a specific site or bodyspace. Orthopedic disorders affecting these locations include, forexample, bursitis, tendonitis, ligamentous pain, chostochondritis,osteoarthritis, and rheumatoid arthritis (or other inflammatory orautoimmune diseases). Bursitis often occurs in multiple differentlocations including, for example, the shoulder (subacromial orsubdeltoid bursitis). Other sites include the olecranon (miners' elbow),prepatellar (housemaid's knee) or suprapatellar, retrocalcaneal(Achilles), iliopectineal (iliopsoas) of the hip, anserine (medialinferior, tibial plateau, ischial (tailor's or weaver's bottom)) of thepelvis, greater trochanteric of the femur, and first metatarsal head(bunion). Bursitis may be caused by trauma, chronic overuse,inflammatory arthritis (e.g., gout, pseudogout, and rheumatoidarthritis, other inflammatory diseases [immune/genetic]), or acute orchronic infection (e.g., pyogenic organisms, particularly Staphylococcusaureus; tuberculosis organisms), as well as post-infectious rheumaticdiseases (e.g., chronic Lyme Disease and post-infectious arthritis).Orthopedic disorders of the foot include, for example, heel spurs,corns, bunions, a neuroma (e.g., Morton's neuroma), arthritis of thefoot (e.g., osteoarthritis), hammertoes, ankle sprain, fractures of theankle or metatarsals or sesamoid bone or toes, plantar fasciitis andinjuries to the Achilles tendon. In certain embodiments, the pain is dueto a bunion.

Orthopedic disorders of the hand include, for example, arthritis, carpaltunnel syndrome, ganglion cysts, tendon problems such as lateralepicondylitis, medial epicondylitis, rotator cuff tendonitis, DeQuervian's tenosynovitis, and trigger finger/trigger thumb. Otherorthopedic disorders include, for example, Paget's disease, scoliosis,soft-tissue injuries such as contusions, sprains and strains, long bonefractures, short bone fractures, small bone fractures, and various othersports or traumatic injuries, some of which include patellar tendonitis,lumbar strain, and cervical strain.

In certain embodiments, the pain is chronic pain. In certainembodiments, the pain is acute pain.

In certain embodiments, the pain arises from the capsule of a joint, adegenerative disc, or a lesion (e.g., a cyst).

In yet other embodiments, the pain is one or more of the types of paindescribed in U.S. Pat. Nos. 5,962,532 and 8,420,600, which are herebyincorporated by reference.

Joint Pain

The pain for treatment may be pain emanating from a joint, such as ajoint selected from the group consisting of knee, elbow, hip,sternoclavicular, temporomandibular, shoulder, spine, wrist, ankle, ajoint in the hand, and a joint in the foot. Accordingly, in certainembodiments, the pain is joint pain. In certain embodiments, the pain ispain in a knee joint, hip joint, shoulder joint, a sterno-manubrialjoint, an acromioclavicular joint, a tempo mandibular joint, elbowjoint, a carpal joint, a tarsal joint, a facet joint, or a metatarsaljoint. In certain embodiments, the pain is pain in a knee joint, hipjoint, shoulder joint, elbow joint, carpal joint, tarsal joint, ormetatarsal joint. In certain embodiments, the joint pain is pain in aknee joint. In certain other embodiments, the joint pain is pain in acarpal joint or a tarsal joint.

In certain embodiments, the patient suffers from an inflammatory,traumatic, post-traumatic, post-surgical, autoimmune, genetic orcongenital defect of the joint. In certain embodiments, the patientsuffers from an inflammatory, autoimmune, genetic or congenital defectof the joint. In certain embodiments, the patient suffers fromosteoarthritis of the joint. In certain other embodiments, the patientsuffers from rheumatoid arthritis of the joint.

In certain embodiments, the joint is an osteoarthritic joint selectedfrom a knee, hip, carpal-metacarpal joint, metatarsal joint, ankle,acromioclavicular joint, wrist, elbow, finger joint, vertebral joint, ortemporal mandibrial joint. In certain embodiments, the joint is anosteoarthritic knee joint.

In a preferred embodiment, the pain to be treated is joint pain in aknee joint affected by osteoarthritis.

In certain other embodiments, the joint is a degenerative disc joint.Exemplary disc joints include a lumbar joint, thoracic joint, orcervical joint.

Route of Administration

The formulations are optimal for administration by injection, though theformulations may be administered by any of the medically accepted routesof administration that a physician of ordinary skill deems safe andappropriate. Exemplary routes of administration include injection into ajoint, injection into a nerve or into tissue in proximity to a nerve,and injection into the spinal canal. In certain embodiments, theadministering comprises injecting the formulation at or near the site ofpain in the patient. In certain embodiments, the administering isintra-articular injection or intrathecal injection. In certainembodiments, the administering is intra-articular injection. In certainembodiments, the administering is intrathecal injection. In certainembodiments, the administering is epidural injection. In certainembodiments, the administering is injection to the spine, such as into aspinal disc.

In yet other embodiments of the therapeutic methods, the administeringcomprises injecting the formulation into a joint to treat joint pain. Inyet other embodiments, the administering comprises injecting theformulation into the intra-articular space of a joint. In yet otherembodiments, the administering comprises injecting the formulation intothe intra-articular space of a knee joint to treat knee joint pain. Inyet other embodiments, the method comprises cooling said joint before,and optionally after, injecting said formulation.

In yet other embodiments, the administering comprises intrathecalinjection of the formulation to the patient.

In certain preferred embodiments, the administering comprises injectingthe formulation into a joint to treat joint pain. In other preferredembodiments, the formulation is administered to the joint byintra-articular injection. In still other preferred embodiments, theadministering comprises injecting the formulation into theintra-articular space of a knee joint to treat knee joint pain, such asosteoarthritic knee joint pain in a human.

In yet other embodiments, the formulation is administered bysubcutaneous delivery, intrathecal delivery, intramuscular delivery,pulmonary delivery, topical delivery (e.g., a gel, ointment, lotion, ortransdermal), oral delivery (e.g., delayed release formulation), orintra-vesicular delivery (e.g., for delivery to a bladder).

Attenuation of Initial Hyperalgesic Effect of Capsaicin

An anesthetic agent can be administered to the patient in order toattenuate any initial hyperalgesic effect caused by administration ofthe capsaicin in the formulation. The anesthetic agent can beadministered directly to the site in which the capsaicin will beadministered, or at a remote site that causes anesthesia at the sitewhere the capsaicin will be administered. For example, epidural regionalanesthesia can be provided to patients to which the capsaicin will beadministered at a site located from the waist down.

In certain embodiments, the anesthetic agent is a caine alkaloid.Exemplary caine alkaloids include lidocaine, dibucaine, bupivacaine,ropivacaine, etidocaine, tetracaine, procaine, chlorocaine, prilocaine,mepivacaine, xylocaine, 2-chloroprocaine, and pharmaceuticallyacceptable salts thereof.

The dose of local anesthetic will depend on the anesthetic beingadministered as well as the site where the local anesthetic isadministered. For example, in embodiments where the local anesthetic isadministered via a regional block (e.g., an ankle block), the dose ofanesthetic may range from about 1 mL up to about 30 mL of a 0.5%solution of anesthetic agent (e.g., bupivacaine). In other embodiments,a dose of up to 5 mg/kg of a solution containing 0.25% to 5% ofanesthetic agent (e.g., lidocaine) may be administered as a nerve block,such as by administration to the site of pain or an area proximal to thesite of pain. In yet other embodiments, the dose of local anesthetic mayrange from about 0.5 mL to about 60 mL of a 0.25% to 5% solution ofanesthetic agent.

In certain embodiments, the anesthetic agent is administered as aproximal, regional, somatic, or neuraxial block. Alternatively, ageneral anesthetic (or other agent that causes sedation) may be used toattenuate any initial hyperalgesic effect caused by administration ofcapsaicin.

In certain other embodiments, any initial pain due to the caspaicininjection may be attenuated by use of an opioid administered orally, orby an alternative systemic route (e.g., intravenously orsubcutaneously).

Accordingly, in one aspect, the therapeutic methods for treating painfurther comprise administering an anesthetic, concurrently or prior tothe aqueous capsaicin injectable formulation, in an amount and locationeffective to attenuate any initial hyperalgesic effect of the capsaicin.In certain embodiments, the anesthetic is a general anesthetic. Incertain embodiments, the anesthetic is a local anesthetic. In certainembodiments, the local anesthetic is a caine alkaloid. In certainembodiments, the local anesthetic is lidocaine or a pharmaceuticallyacceptable salt thereof.

Additional description of procedures and agents that may be used toattenuate any initial hyperalgesic effect caused by administration ofthe capsaicin-containing formulation are described in U.S. Pat. No.5,962,532, which is hereby incorporated by reference.

Patients for Treatment

The method may be further characterized according to the patient to betreated. Accordingly, in certain embodiments, the patient is an adulthuman. In other embodiments, the patient is a canine.

Duration of Pain Relief

The method may be further characterized according to the duration ofpain relief provided. For example, in certain embodiments, the methodprovides relief from said pain for a duration of at least 3 months. Inother embodiments, the method provides relief from said pain for aduration of at least 6 months. In other embodiments, the method providesrelief from said pain for a duration of from about 1 month to about 9months, from about 3 months to about 9 months, from about 3 months toabout 7 months, or about 3 months to about 6 months.

Dose of Capsaicin Administered to the Patient

The dose of capsaicin administered to the patient may depend on, forexample, the type of pain to be treated and may be selected according todose-selection procedures known to those skilled in the art. In certainembodiments, the dose of capsaicin administered to a patient as a singleadministration is from about 1 μg to about 5000 μg, from about 250 μg toabout 2000 μg, or 500 μg to about 1000 μg. In certain embodiments, theadministering is injecting at or near the site of pain a single dose ofthe capsaicin in an amount of from about 1 μg to about 5000 μg. Incertain embodiments, the administering is injecting at or near the siteof pain a single dose of the capsaicin in an amount of from about 250 μgto about 2000 μg. In certain embodiments, the administering is injectingat or near the site of pain a single dose of the capsaicin in an amountof from about 500 μg to about 1000 μg. In certain embodiments, theadministering is injecting at or near the site of pain a single dose ofthe capsaicin in an amount of about 1000 μg.

V. Kits for Use in Medical Applications

Another aspect of the invention provides a kit for treating a disorder.The kit comprises: i) instructions for treating pain, such asosteoarthritic knee joint pain; and ii) an aqueous capsaicin injectableformulation described herein, such as one of the formulations describedin Tables 1-5.

The description above describes multiple aspects and embodiments of theinvention. The patent application specifically contemplates allcombinations and permutations of the aspects and embodiments.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1 Analysis of Capsaicin Solubility of Multiple AqueousFormulations Containing a Solubilizing Agent

Multiple aqueous formulations were prepared and analyzed to determinethe amount of dissolved capsaicin. The formulations contained differentsolubilizing agents to increase the amount of capsaicin dissolved in theaqueous medium. The experimental procedures and results are describedbelow.

Part I—Analysis of Capsaicin Solubility in Multiple Aqueous Formulations

Aqueous formulations were prepared containing capsaicin and asolubilizing agent selected from Tween 20, Tween 80, Kolliphor ELP,Kolliphor HS 15, Kollidon 12 PF, and Kollidon 17 PF as further definedbelow. Experimental procedures and results are described below.

Experimental Procedures

The equilibrium solubility of capsaicin was determined in a series ofaqueous solutions. Six different types of vehicles were prepared atthree different concentrations each. Tween 20 solutions were prepared ata range of 0.2% to 10% (w/v). Tween 80 solutions were prepared at arange of 0.2% to 1.0% (w/v). Kolliphor ELP and Kolliphor HS 15 solutionswere both prepared at a range of 5% to 20% (w/v). Kollidon 12 PFsolutions were prepared at a range of 2.5% to 10% (w/v). Kollidon 17 PFsolutions were prepared at a range of 0.5% to 2.0% (w/v).

For each test solution, quantities of 20-30 mg of capsaicin were addedto a micro centrifuge tubes. A volume of 1.5 mL of the appropriate testvehicle was added to each to create a suspension. The capped tubes weremixed on a laboratory rotator at ambient temperature. At approximately48 hours after sample preparation, the tubes were removed from therotator and centrifuged to separate the solid phase from the solution.An aliquot of the supernatant was withdrawn from each sample and dilutedas necessary for HPLC analysis to determine the solution concentrationof the capsaicin. The pH of the supernatant was measured 48 hours afterpreparation and the appearance of solid and supernatant were noted.

As reported in the literature, Tween 20 is also known as Polysorbate 20,which has the chemical name polyoxyethylene (20) sorbitan monolaurate.Tween 80 is also known as Polysorbate 80, which has the chemical namepolyoxyethylene (20) sorbitan monooleate. Kolliphor ELP has CAS RegistryNo. 61791-12-6, and is a composition sold by BASF under the chemicalname polyoxyl-35-castor oil and marketed by BASF as Kolliphor™ ELP; thecomposition is made by reacting castor oil with ethylene oxide in amolar ratio of 1:35. The Kolliphor HS 15 has CAS Registry No.70142-34-6, and is a mixture containing (a) about 70% (w/w) of a mixtureof

and (b) about 30% (w/w) polyethylene glycol; where the polyethyleneglycolyl has a weight-average molecular weight of about 660 g/mol; whichis sold and marketed by BASF as KOLLIPHOR® HS 15. Kollidon 12 PF is apolyvinylpyrrolidone having a weight-average molecular weight in therange of 2,000 to 3,000 g/mol, sold by BASF under the name KOLLIDON® 12PF. Kollidon 17 PF is a polyvinylpyrrolidone having a weight-averagemolecular weight in the range of 7,000 to 11,000 g/mol, sold by BASFunder the name KOLLIDON® 17 PF.Results

Results from the above analysis are presented in Table 6. For all testsolutions except those containing Kollidon12 PF or Kollidon17 PF, theobserved concentration of capsaicin increased concordant with increasingsurfactant concentration. With the exception of Kollidon 12 PF andKollidon 17 PF, at least one test solution from each of differentsolubilizing agents reached the minimum target concentration ofcapsaicin of 1 mg/mL capsaicin. Both Kollidon 12 PF and Kollidon 17 PFsolutions, at all strengths, failed to reach the minimum targetconcentration of 1 mg/mL capsaicin. The highest concentrations ofcapsaicin were observed in the 20% strength Kolliphor ELP{c(Capsaicin)=13.0 mg/mL} and 20% Kolliphor HS 15 {c(Capsaicin)=12.2mg/mL} solutions.

The observed pH-values in the supernatants of the test solutions rangedfrom pH=3.88 to pH=7.27. Appearances of both the liquid supernatant andthe remaining solid were observed to be clear and as at initial solutionpreparation. For all samples that had remaining solid, the solidappeared white and had no notable difference from its startingconsistency.

After centrifugation of the sample containing 20% Kolliphor ELP no solidresidue could be detected, which signifies that the equilibriumsolubility for Capsaicin in this vehicle was not reached and is greaterthan the observed c(Capsaicin)=13.0 mg/mL. For the 20% Kolliphor HSvehicle, the amount of pelleted solid from centrifugation was at thelimit of detection.

TABLE 6 appear- Sample Observed pH appear- ance (amount in weight[Capsaicin] (at ance super- percent) (mg/mL) 48 hr) pellet natant Tween20 (0.2%) 0.146 6.78 white clear Tween 20 (2%) 1.11 6.16 white clearTween 20 (10%) 5.39 6.03 white clear Tween 80 (0.2%) 0.233 6.45 whiteclear Tween 80 (0.5%) 0.245 7.27 white clear Tween 80 (1.0%) 1.00 7.03white clear Kolliphor ELP (5%) 4.20 5.61 white clear Kolliphor ELP (10%)8.14 5.21 white clear Kolliphor ELP (20%) 13.0 4.70 none clear KolliphorHS 15 (5%) 3.81 6.65 white clear Kolliphor HS 15 (10%) 7.18 6.97 whiteclear Kolliphor HS 15 (20%) 12.2 7.01 white clear Kollidon 12 (2.5%)0.276 4.22 white clear Kollidon 12 (5%) 0.624 4.00 white clear Kollidon12 (10%) 0.378 3.88 white clear Kollidon 17 (0.5%) 0.150 5.75 whiteclear Kollidon 17 (1.0%) 0.247 4.66 white clear Kollidon 17 (2.0%) 0.1994.20 white clearPart II—Capsaicin Solubility in Cyclodextrin Solutions

Aqueous formulations were prepared containing capsaicin and asolubilizing agent selected from hydroxypropyl-β-cyclodextrin andcaptisol (i.e., sodium sulfobutyl ethers β-cyclodextrin). Experimentalprocedures and results are described below.

Experimental Procedures

For each cyclodextrin solution, quantities of about 20-30 mg ofcapsaicin were suspended in 1.5 mL of the respective cyclodextrinsolution. The capped tubes were mixed on a laboratory rotator at ambienttemperature. At approximately 48 hours after sample preparation, thetubes were removed from the rotator and centrifuged to separate thesolid phase from the solution. An aliquot of the supernatant waswithdrawn from each sample and diluted as necessary for HPLC analysis todetermine the solution concentration of the capsaicin, which wasquantitated relative to the reference standard. The pH of thesupernatant was measured and the appearance of both the supernatant andthe solid were noted at 48 hours.

Results

Results from the above analysis are presented in Table 7. For bothcyclodextrins tested, at all solution strengths, at least 2 mg/mLcapsaicin was observed. Hydroxypropyl-β-cyclodextrin had slightly higherconcentrations of capsaicin than captisol for all solution strengths.The pH of the solutions ranged from 7.00 to 7.94. The liquid portion ofeach sample was clear and appeared unchanged from its original state.The solid portion of each sample was white, granular, and appeared as itdid prior to the addition of the cyclodextrin solution. The 25%solutions of both cyclodextrins had very little remaining solid.

TABLE 7 appear- Observed appea- ance pH Peak area [Capsaicin], rancesuper- (at Sample (mAU) mg/mL pellet natant 48 hr) 5% Hydroxy- 42479052.39 White clear 7.32 propyl-β- cyclodextrin 10% Hydroxy- 7891725 4.45White clear 7.44 propyl-β- cyclodextrin 25% Hydroxy- 20541037 11.6 Whiteclear 7.00 propyl-β- cyclodextrin 5% Captisol 3734548 2.10 White clear7.94 10% Captisol 6561988 3.70 White clear 7.65 25% Captisol 146602168.26 White clear 7.23Part III—Capsaicin Solubility in Additional Aqueous Solutions

Aqueous formulations were prepared containing capsaicin and an additive.The solubility of capsaicin was also analyzed in deionized water.Experimental procedures and results are described below.

Experimental Procedures

For each of the six solutions, quantities of about 20-30 mg of capsaicinwere added to each of six micro centrifuge tubes. A volume of 1.5 mL ofthe appropriate solution was added to each to create a suspension. Thecapped tubes were mixed on a laboratory rotator at ambient temperature.At approximately 7 days after sample preparation, the tubes were removedfrom the rotator and centrifuged to separate the solid phase from thesolution. An aliquot of the supernatant was withdrawn from each sampleand diluted as necessary for HPLC analysis to determine the solutionconcentration of the capsaicin, which was quantitated relative to thereference standard. The pH-values of the supernatant were measured andthe appearance of both the supernatant and the pelleted solid werenoted.

Results

Results from the above analysis are presented in Table 8. The lowestconcentration of the capsaicin was observed in deionized water withc(Capsaicin)=7.6 μg/mL while solubilization of capsaicin in aqueous 2.5%glycerol resulted in the highest observed concentration of capsaicinwith c(Capsaicin)=38 μg/mL.

TABLE 8 appear- Observed appear- ance pH Peak area [Capsaicin], ancesuper- (at Sample (mAU) mg/mL pellet natant 7 days) Water 135565 0.008White clear 4.53 5% mannitol 381253 0.021 White clear 5.53 5% mannitol,513817 0.020 White clear 4.73 0.1M pH 5 Citrate 5% mannitol, 3781480.021 White clear 5.86 0.1M pH 6 Citrate 5% mannitol, 484164 0.027 Whiteclear 5.25 0.1M pH 5 Acetate 2.5% glycerol in 682320 0.038 White clear6.47 water

Example 2 Stability Analysis of Exemplary Formulations

The aqueous formulations in Table 9 below were subjected to stabilityanalysis by storage at 5° C., 25° C., 40° C., and/or 60° C., followed byanalytical analysis to determine the amount of capsaicin and/orimpurities in the formulation. Results are provided below. Theabbreviation BHT refers to dibutylhydroxytoluene. The abbreviation“EDTA” refers to ethylenediaminetetraacetic acid. The Kolliphor HS-15has CAS Registry No 70142-34-6, and is a mixture containing (a) about70% (w/w) of a mixture of

and (b) about 30% (w/w) polyethylene glycol; where the polyethyleneglycolyl has a weight-average molecular weight of about 660 g/mol; whichis sold and marketed by BASF as KOLLIPHOR® HS 15. The phrase “AverageParticles Per Container” refers to the average number of particlesobserved in a container, where the container held approximately 1.5 mLof aqueous formulation to be analyzed.

TABLE 9 Solution 1A: Solution 1P: 1 mg/ml Capsaicin 2% Kolliphor HS-152% Kolliphor HS-15 20 mM citrate buffer 20 mM citrate buffer 0.1%disodium EDTA 0.1% disodium EDTA 0.01% BHT 0.01% BHT 0.625% NaCl 0.625%NaCl q.s. water q.s. water Solution 2A: Solution 3A: 2 mg/ml Capsaicin 1mg/ml Capsaicin 4% Kolliphor HS-15 2% Kolliphor HS-15 20 mM citratebuffer 0.1% disodium EDTA 0.1% disodium EDTA 0.01% BHT 0.01% BHT 3.15%Dextrose 0.625% NaCl q.s. water q.s. water Solution 3P: Solution 4A: 2%Kolliphor HS-15 2 mg/ml Capsaicin 20 mM citrate buffer 4% KolliphorHS-15 0.1% disodium EDTA 20 mM citrate buffer 0.01% BHT 0.1% disodiumEDTA 3.15% Dextrose 0.01% BHT q.s. water 3.15% Dextrose q.s. water

TABLE 1A Summary of results for the Solution 1A formulation at 5° C.Average Average HPLC Testing Particles Particles Purity, time, Solution1A Per Per Conc., Area % 5° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 1.0 873 1856 1842 colorless(0.003%) (0.005%) (0.005%) 1¹ 3² 6¹ Clear and 5.5 1.0 N/A N/A 1864colorless (0.005%) Testing time, 5° C. Peak 4, Peak 5, Peak 6, Peak 7,Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8 min 20.5 min 20.9 min37.7 min 0¹ 1031 1751 5490 30126 34429382 28100  (0.003%) (0.005%)(0.016%) (0.087%) (99.794%) (0.081%) 1¹ 3² 6¹ N/A N/A N/A N/A 339139178866 (99.870%) (0.026%) ¹Performed on HPLC10 ²Performed on HPLC12(B)

TABLE 2A Summary of results for the Solution 1A formulation at 25° C.Average Average HPLC Testing Particles Particles Purity, time, Solution1A Per Per Conc., Area % 25° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 19.40 1.10 1.0 N/A 1858 1834colorless (0.005%) (0.005%) 1¹ Clear and 5.5 1.0 678 1881 1844 colorless(0.002%) (0.005%) (0.006%) 3² Clear and 5.5 0.9 N/A 2151 4995 colorless(0.007%) (0.016%) 6¹ Clear and 5.5 40.60 1.30 1.0 N/A 1759 1914colorless (0.005%) (0.006%) Testing time, 25° C. Peak 4, Peak 5, Peak 6,Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8 min 20.5 min20.9 min 37.7 min 0¹  886 2919 7432 32759 34570267 23242  (0.003%)(0.008%) (0.021%) (0.095%) (99.795%) (0.067%) 1¹ 1073 1538 5778 3066534565985 7828 (0.003%) (0.004%) (0.017%) (0.089%) (99.852%) (0.023%) 3²1642 2491 4649 35711 31442165 21338  (0.004%) (0.008%) (0.015%) (0.113%)(99.631%) (0.068%) 6¹ N/A N/A N/A N/A 33979632 6676 (99.871%) (0.020%)¹Performed on HPLC10 ²Performed on HPLC12(C)

TABLE 2A-1 Additional peaks for Solution 1A formulation at 25° C. at t =3 months. HPLC Purity, T = 3 m extra Area % peaks Peak @ Peak @ Peak @7.9 min 15.3 min 34.4 min 14113 6702 4917 (0.045%) (0.021%) (0.014%)(D)

TABLE 3A Summary of results for the Solution 1A formulation at 40° C.Average Average HPLC Testing Particles Particles Purity, time, Solution1A Per Per Conc., Area % 40° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 45.80 2.00 1.0 N/A 1923 1856 colorless (0.006%) (0.005%) 1¹ Clear and 5.5 1.0  677 2146 1898 colorless (0.002%) (0.006%) (0.005%) 3² Clear and 5.5 0.9 1591 3347 4381colorless (0.005%) (0.011%) (0.016%) 6¹ Clear and 5.5 66.70 1.70 1.0 N/A10294  1654 colorless (0.030%) (0.005%) Testing time, 40° C. Peak 4,Peak 5, Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8min 20.5 min 20.9 min 37.7 min 0¹ 985 2006 6269 30643 34576418 7561(0.003%) (0.006%) (0.018%) (0.088%) (99.852%) (0.022%) 1¹ 928 1871 573030312 34727820 11056  (0.003%) (0.005%) (0.016%) (0.087%) (99.843%)(0.032%) 3² 1668  2218 4523 32761 30846401 17222  (0.005%) (0.007%)(0.015%) (0.106%) (99.642%) (0.056%) 6¹ N/A N/A N/A 29082 33990190 5366(0.085%) (99.841%) (0.016%) ¹Performed on HPLC10 ²Performed on HPLC12(E)

TABLE 3A-1 Additional peaks for Solution 1A formulation at 40° C. at t =3 months. HPLC Purity, T = 3 m extra Area % peaks Peak @ Peak @ 7.9 min15.3 min 13886 5885 (0.045%) (0.019%)(F)

TABLE 3A-2 Additional peaks for Solution 1A formulation at 40° C. at t =6 months. HPLC Purity, Area % T = 6 m extra Peak @ peaks 7.9 min — 3717— (0.011%)(G)

TABLE 4A Summary of results for the Solution 1A formulation at 60° C.Average Average HPLC Testing Particles Particles Purity, time, Solution1A Per Per Conc., Area % 60° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 1.0 656 2174 2035  colorless(0.002%) (0.006%) (0.006%) 1¹ Cloudy, 5.5 1.0 892 3336 627 then clears(0.003%) (0.01%) (0.002%) up after 5 min 3 6 Testing time, 60° C. Peak4, Peak 5, Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min16.8 min 20.5 min 20.9 min 37.7 min 0¹ 1391  2705 6913 29898 343486436216 (0.004%) (0.008%) (0.020%) (0.087%) (99.849%) (0.018%) 1¹ 853 17054910 30368 34698973 11505  (0.002%) (0.005%) (0.014%) (0.087%) (99.829%)(0.033%) 3 6 ¹Performed on HPLC10(H)

TABLE 5A Summary of results for the Solution 1P formulation at 5° C.Average Average HPLC Testing Particles Particles Purity, time, Solution1P Per Per Conc., Area % 5° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.2 0 527 N/A N/A colorless (100%)1 3 6¹ Clear and 5.2 0 N/A N/A N/A colorless Testing time, 5° C. Peak 4,Peak 5, Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8min 20.5 min 20.9 min 37.7 min 0¹ N/A N/A N/A N/A N/A N/A 1 3 6¹ N/A N/AN/A N/A N/A N/A ¹Performed on HPLC10(I)

TABLE 5A-1 Additional peaks for Solution 1P formulation at 5° C. at t =1 month. HPLC Purity, Area % T = 1 m extra Peak @ peaks 39.8 min — 7691— (91.462%)(J)

TABLE 6A Summary of results for the Solution 1P formulation at 25° C.Average Average HPLC Testing Particles Particles Purity, time, Solution1P Per Per Conc., Area % 25° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.3 15.70 0.60 0 693 N/A N/Acolorless (100%) 1¹ Clear and 5.3 0 697 N/A N/A colorless (100%) 3²Clear and 5.3 0 N/A N/A N/A colorless 6¹ Clear and 5.3 33.70 1.10 0 N/AN/A N/A colorless Testing time, 25° C. Peak 4, Peak 5, Peak 6, Peak 7,Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8 min 20.5 min 20.9 min37.7 min 0¹ N/A N/A N/A N/A N/A N/A 1¹ N/A N/A N/A N/A N/A N/A 3² N/AN/A N/A 22037 N/A 21266 (34.748%) (33.532%) 6¹ N/A N/A N/A N/A N/A N/A¹Performed on HPLC10 ²Performed on HPLC12(K)

TABLE 6A-1 Additional peaks for Solution 1P formulation at 25° C. at t =3 months. HPLC Purity, T = 3 m extra Area % peaks Peak @ Peak @ 7.9 min15.3 min 11261 8856 17.756%) (13.964%)(L)

TABLE 7A Summary of results for the Solution 1P formulation at 40° C.Average Average HPLC Testing Particles Particles Purity, time, Solution1P Per Per Conc., Area % 40° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.3 26.00 1.20 0 N/A N/A N/Acolorless 1¹ Clear and 5.3 0 570 N/A N/A colorless (100%) 3² Clear and5.3 0 N/A N/A N/A colorless 6¹ Clear and 5.3 64.60 3.20 0 N/A N/A N/Acolorless Testing time, 40° C. Peak 4, Peak 5, Peak 6, Peak 7, CapsaicinPeak 8, (months) 9.1 min 13.6 min 16.8 min 20.5 min 20.9 min 37.7 min 0¹N/A N/A N/A N/A N/A N/A 1¹ N/A N/A N/A N/A N/A N/A 3² N/A N/A N/A 20712N/A 18573 (40.96%) (36.729%) 6¹ N/A N/A N/A N/A N/A N/A ¹Performed onHPLC10 ²Performed on HPLC12(M)

TABLE 7A-1 Additional peaks for Solution 1P formulation at 40° C. at t =3 months. HPLC Purity, T = 3 m extra Area % peaks Peak @ Peak @ 7.9 min34.4 min 9574 1708 (18.933%) (0.061%)(N)

TABLE 8A Summary of results for the Solution 1P formulation at 60° C.Average Average HPLC Testing Particles Particles Purity, time, Solution1P Per Per Conc., Area % 60° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.2 0 N/A N/A N/A colorless 1¹Cloudy, 5.3 0 N/A N/A N/A then clears up after 5 min 3 6 Testing time,60° C. Peak 4, Peak 5, Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1min 13.6 min 16.8 min 20.5 min 20.9 min 37.7 min 0¹ N/A N/A N/A N/A N/AN/A 1¹ N/A N/A N/A N/A N/A N/A 3 6 ¹Performed on HPLC10(O)

TABLE 9A Summary of results for the Solution 2A formulation at 5° C.Average Average HPLC Testing Particles Particles Purity, time, Solution2A Per Per Conc., Area % 5° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 1.7 2079 4943 4018 colorless(0.003%) (0.008%) (0.006%) 1 3 6¹ Clear and 5.5 1.7 N/A 5008 6050colorless (0.009%) (0.010%) Testing time, 5° C. Peak 4, Peak 5, Peak 6,Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8 min 20.5 min20.9 min 37.7 min 0¹ 2496 4587 13424 60045 62109784 26991 (0.004%)(0.007%) (0.022%) (0.096%) (99.808%) (0.043%) 1 3 6¹ 2337 4423 N/A 5202259537951 11323 (0.004%) (0.007%) (0.087%) (99.897%) (0.019%) ¹Performedon HPLC10(P)

TABLE 10A Summary of results for the Solution 2A formulation at 25° C.Average Average HPLC Testing Particles Particles Purity, time, Solution2A Per Per Conc., Area % 25° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.6 16.60 0.40 1.7 1857 4780 4327colorless (0.003%) (0.008%) (0.007%) 1¹ Clear and 5.5 1.7 2868 6146 6318colorless (0.005%) (0.010%) (0.010%) 3² Clear and 5.5 1.6 2901 662112531  colorless (0.005%) (0.012%) (0.023%) 6¹ Clear and 5.5 38.00 1.001.7 N/A 6247 6786 colorless (0.010%) (0.011%) Testing time, 25° C. Peak4, Peak 5, Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min16.8 min 20.5 min 20.9 min 37.7 min 0¹ 2490 5098 13402 60901 621583076972 (0.004%) (0.008%) (0.021%) (0.098%) (99.819%) (0.003%) 1¹ 2434 482912911 60510 62234585 6741 (0.004%) (0.008%) (0.021%) (0.097%) (99.804%)(0.011%) 3² 3404 5277 10081 56265 54007764 24506  (0.005%) (0.010%)(0.019%) (0.104%) (99.608%) (0.043%) 6¹ 1771 N/A N/A N/A 59784009 5665(0.003%) (99.828%) (0.009%) ¹Performed on HPLC10 ²Performed on HPLC12(Q)

TABLE 10A-1 Additional peaks for Solution 2A formulation at 25° C. at t= 1 month. HPLC Purity, T = 1 m extra Area % peaks Peak @ Peak @ 18.8min 36.6 min 6874 1581 (0.0117%) (0.003%)(R)

TABLE 10A-2 Additional peaks for Solution 2A formulation at 25° C. at t= 3 months. HPLC Purity, T = 3 m extra Area % peaks Peak @ Peak @ Peak @7.2 min 7.9 min 15.3 min 3084 15264 13630 (0.005%) (0.028%) (0.025%)(S)

TABLE 11A Summary of results for the Solution 2A formulation at 40° C.Average Average HPLC Testing Particles Particles Purity, time, Solution2A Per Per Conc., Area % 40° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.6 10.90 0.80 1.7 2010 5711 4450colorless (0.003%) (0.009%) (0.007%) 1¹ Clear and 5.6 1.7 2747 6962 5969colorless (0.004%) (0.011%) (0.010%) 3² Clear and 5.5 1.6 3635 856010898  colorless (0.006%) (0.016%) (0.020%) 6¹ Clear and 5.5 46.00 1.801.7 2453 13974  6867 colorless (0.004%) (0.023%) (0.011%) Testing time,40° C. Peak 4, Peak 5, Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1min 13.6 min 16.8 min 20.5 min 20.9 min 37.7 min 0¹ 2426 5381 1524160560 62197853 6605 (0.004%) (0.009%) (0.024%) (0.097%) (99.834%)(0.011%) 1¹ 2691 4826 12928 60894 62203800 12505  (0.004%) (0.008%)(0.021%) (0.098%) (99.815%) (0.02%)  3² 2844 4836 13765 60708 5381801231825  (0.004%) (0.009%) (0.025%) (0.112%) (99.639%) (0.059%) 6¹ 1818N/A N/A 50941 59771249 4219 (0.003%) (0.085%) (99.816%) (0.007%)¹Performed on HPLC10 ²Performed on HPLC12(T)

TABLE 11A-1 Additional peaks for Solution 2A formulation at 40° C. at t= 1 month HPLC Purity, T = 1 m extra Area % peaks Peak @ Peak @ Peak @5.0 min 5.9 min 36.6 min 2084 1503 940 (0.003%) (0.002%) (0.002%)(U)

TABLE 11A-2 Additional peaks for Solution 2A formulation at 40° C. at t= 3 months. HPLC Purity, T = 3 m extra Area % peaks Peak @ Peak @ Peak @Peak @ Peak @ 5.7 min 7.2 min 7.9 min 16.7 min 38.3 min 3988 3616 132889899 3566 (0.007%) (0.004%) (0.025%) (0.018%) (0.004%)(V)

TABLE 11A-3 Additional peaks for Solution 2A formulation at 40° C. at t= 6 months. HPLC Purity, T = 3 m extra Area % peaks Peak @ Peak @ Peak @Peak @ Peak @ 5.7 min 7.2 min 7.9 min 16.7 min 38.3 min 6021 N/A N/A N/A3566 (0.010%) (0.004%)(W)

TABLE 12A Summary of results for the Solution 2A formulation at 60° C.Average Average HPLC Testing Particles Particles Purity, time, Solution2A Per Per Conc., Area % 60° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 1.7 1667 6124 4951 colorless(0.003%) (0.010%) (0.008%) 1¹ Cloudy, 5.6 1.7 2898 3180 3313 then clears(0.005%) (0.005%) (0.005%) up after 5 min 3 6 Testing time, 60° C. Peak4, Peak 5, Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min16.8 min 20.5 min 20.9 min 37.7 min 0¹ 2328 5116 13236 59443 616674567725 (0.004%) (0.008%) (0.021%) (0.096%) (99.837%) (0.013%) 1¹ 27884.565 12218 61038 62306234 8570 (0.004%) (0.007%) (0.020%) (0.098%)(99.768%) (0.014%) 3 6 ¹Performed on HPLC10(X)

TABLE 12A-1 Additional peaks for Solution 2A formulation at 60° C. at t= 1 month. HPLC Purity, T = 1 m extra Area % peaks Peak @ Peak @ Peak @Peak @ Peak @ Peak @ Peak @ 5.0 min 5.1 min 5.56 min 5.9 min 6.9 min 7.4min 9.0 min 3173 1574 9340 8799 2986 4115 732 (0.005%) (0.003%) (0.015%)(1.014%) (0.005%) (0.007%) (0.001%)(Y)

TABLE 13A Summary of results for the Solution 3A formulation at 5° C.Average Average HPLC Testing Particles Particles Purity, time, Solution3A Per Per Conc., Area % 5° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 0.9 N/A 2228 1921 colorless(N/A) (0.007%) (0.006%) 1 3 6¹ Clear and 5.5 0.9 N/A 2341 2163 colorless(0.007%) (0.006%) Testing time, 5° C. Peak 4, Peak 5, Peak 6, Peak 7,Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8 min 20.5 min 20.9 min37.7 min 0¹ 879 2539 5549 27041 33868383 27763  (0.003%) (0.007%)(0.016%) (0.080%) (99.800%) (0.082%) 1 3 6¹ N/A N/A N/A N/A 332434048292 (99.865%) (0.025%) ¹Performed on HPLC10(Z)

TABLE 14A Summary of results for the Solution 3A formulation at 25° C.Average Average HPLC Testing Particles Particles Purity, time, Solution3A Per Per Conc., Area % 25° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 24.10 0.60 1.0 978 2398 1865colorless (0.003%) (0.007%) (0.005%) l¹ Clear and 5.5 0.9 987 2880 2776colorless (0.003%) (0.008%) (0.008%) 3² Clear and 5.5 0.9 N/A 3139 5626colorless (0.010%) (0.018%) 6¹ Clear and 5.5 36.50 1.00 0.9 N/A 29172113 colorless (0.009%) (0.006%) Testing time, 25° C. Peak 4, Peak 5,Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8 min20.5 min 20.9 min 37.7 min 0¹ 1091 1958 5624 28586 34141239 13128 (0.003%) (0.006%) (0.016%) (0.094%) (99.837%) (0.038%) l¹ 1286 2786 712829003 33940156 7013 (0.004%) (0.008%) (0.021%) (0.085%) (99.829%)(0.021%) 3² N/A 2484 4551 32787 30862935 21336  (0.008%) (0.015%)(0.106%) (99.646%) (0.069%) 6¹ N/A N/A N/A N/A 33384663 3199 (99.881%)(0.010%) ¹Performed on HPLC10 ²Performed on HPLC12(AA)

TABLE 14A-1 Additional peaks for Solution 3A formulation at 25° C. at t= 1 month. HPLC Purity, T = 1 m extra Area % peaks Peak @ Peak @ Peak @4.4 min 5.0 min 39.8 min 987 3934 244 (0.003%) (0.012%) (0.001%)(BB)

TABLE 14A-2 Additional peaks for Solution 3A formulation at 40° C. at t= 3 months. HPLC Purity, T = 3 m extra Area % peaks Peak @ Peak @ Peak @7.9 min 15.3 min 36.8 min 14151 6463 6734 (0.046%) (0.021%) (0.022%)(CC)

TABLE 15A Summary of results for the Solution 3A formulation at 40° C.Average Average HPLC Testing Particles Particles Purity, time, Solution3A Per Per Conc., Area % 40° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 22.00 1.00 0.9 855 2876 2098colorless (0.003%) (0.008%) (0.006%) 1¹ Clear and 5.5 0.9 730 2941 1604colorless (0.002%) (0.009%) (0.005%) 3² Clear and 5.5 0.9 6789  512513881  colorless (0.023%) (0.017%) (0.045%) 6¹ Clear and 5.5 57.90 1.500.9 N/A 8800 N/A colorless (0.026%) Testing time, 40° C. Peak 4, Peak 5,Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8 min20.5 min 20.9 min 37.7 min 0¹ 1006  2701 7437 29878 34007216 7294(0.003%) (0.008%) (0.022%) (0.088%) (99.841%) (0.080%) 1¹ 931 1592 530629304 33926903 10987  (0.003%) (0.005%) (0.016%) (0.086%) (99.839%)(0.032%) 3² N/A 2261 5441 31138 30598360 21509  (0.007%) (0.018%)(0.101%) (99.561%) (0.058%) 6¹ N/A N/A N/A 26116 33379272 6201 (0.078%)(99.791%) (0.019%) ¹Performed on HPLC10 ²Performed on HPLC12(DD)

TABLE 15A-1 Additional peaks for Solution 3A formulation at 40° C. at t= 1 month. HPLC Purity, Area % T = 1 m extra Peak @ peaks 3.1 min — 1365— (0.004%)(EE)

TABLE 15A-2 Additional peaks for Solution 3A formulation at 40° C. at t= 3 months. HPLC Purity, T = 3 m extra Area % peaks Peak @ Peak @ Peak @Peak @ Peak @ Peak @ 4.8 min 5.7 min 7.2 min 8.1 min 16.7 min 36.8 min7856 2711 2788 3786 4299 6734 (0.023%) (0.008%) (0.008%) (0.012%)(0.014%) (0.022%)(FF)

TABLE 15A-3 Additional peaks for Solution 3A formulation at 40° C. at t= 6 months. HPLC Purity, Area % T = 6 m extra Peak @ peaks 5.7 min —4261 — (0.013%)(GG)

TABLE 16A Summary of results for the Solution 3A formulation at 60° C.Average Average HPLC Testing Particles Particles Purity, time, Solution3A Per Per Conc., Area % 60° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 0.9 960 3048 2309 colorless(0.003%) (0.009%) (0.007%) 1¹ Cloudy, 5.6 0.9 2403  3683 N/A then clears(0.007%) (0.011%) up after 5 min 3 6 Testing time, 60° C. Peak 4, Peak5, Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8 min20.5 min 20.9 min 37.7 min 0¹ 1379 1731 5375 29049 33529633 7715(0.004%) (0.005%) (0.016%) (0.087%) (99.846%) (0.023%) 1¹ 1961 1447 304129174 33932823 10919  (0.006%) (0.004%) (0.009%) (0.085%) (99.249%)(0.032%) 3 6 ¹Performed on HPLC10(HH)

TABLE 16A-1 Additional peaks for Solution 3A formulation at 60° C. at t= 1 month. HPLC Purity, T = 1 m extra Area % peaks Peak @ Peak @ Peak @Peak @ Peak @ Peak @ Peak @ Peak @ Peak @ 3.1 min 3.9 min 5.1 min 5.56min 5.9 min 6.9 min 7.4 min 9.0 min 25.7 min 163418 2403 1015 7846 50222962 3107 3314 14985 (0.478%) (0.007%) (0.003%) (0.023%) (0.015%)(0.009%) (0.009%) (0.010%) (0.044%)(II)

TABLE 17A Summary of results for the Solution 3P formulation at 5° C.Average Average HPLC Testing Particles Particles Purity, time, Solution3P Per Per Conc., Area % 5° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 0 609 N/A N/A colorless (100%)1 3 6¹ Clear and 5.5 0 N/A N/A N/A colorless Testing time, 5° C. Peak 4,Peak 5, Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8min 20.5 min 20.9 min 37.7 min 0¹ N/A N/A N/A N/A N/A N/A 1 3 6¹ N/A N/AN/A N/A N/A N/A ¹Performed on HPLC10(JJ)

TABLE 18A Summary of results for the Solution 3P formulation at 25° C.Average Average HPLC Testing Particles Particles Purity, time, Solution3P Per Per Conc., Area % 25° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 18.90 1.20 0 N/A N/A N/Acolorless 1¹ Clear and 5.5 0 636 N/A N/A colorless (100%) 3² Clear and5.5 0 N/A N/A 11254 colorless (22.927%) 6¹ Clear and 5.5 42.90 2.20 0N/A N/A N/A colorless Testing time, 25° C. Peak 4, Peak 5, Peak 6, Peak7, Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8 min 20.5 min 20.9min 37.7 min 0¹ N/A N/A N/A N/A N/A N/A 1¹ N/A N/A N/A N/A N/A N/A 3²N/A N/A N/A 20892 N/A 16940 (42.562%) (34.511%) 6¹ N/A N/A N/A N/A N/AN/A ¹Performed on HPLC10 ²Performed on HPLC12(KK)

TABLE 19A Summary of results for the Solution 3P formulation at 40° C.Average Average HPLC Testing Particles Particles Purity, time, Solution3P Per Per Conc., Area % 40° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 17.10 0.80 0 N/A N/A N/Acolorless 1¹ Clear and 5.5 0 1594 N/A N/A colorless (51.041%) 3² Clearand 5.5 0 N/A N/A 9421 colorless (12.884%) 6¹ Clear and 5.5 49.50 1.70 0N/A N/A N/A colorless Testing time, 40° C. Peak 4, Peak 5, Peak 6, Peak7, Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8 min 20.5 min 20.9min 37.7 min 0¹ N/A N/A N/A N/A N/A N/A 1¹ N/A N/A N/A N/A N/A N/A 3²N/A N/A N/A 22140 N/A 25435  (30.279%) (34.785%) 6¹ N/A N/A N/A N/A N/A4955 (11.855%) ¹Performed on HPLC10 ²Performed on HPLC12(LL)

TABLE 19A-1 Additional peaks for Solution 3P formulation at 40° C. at t= 1 month. HPLC Purity, Area % T = 1 m extra Peak @ peaks 3.1 min — 1529— (48.959%)(MM)

TABLE 19A-2 Additional peaks for Solution 3P formulation at 40° C. at t= 3 months. HPLC Purity, Area % T = 3 m extra Peak @ peaks 22.8 min —14492 — (19.819%)(NN)

TABLE 19A-3 Additional peaks for Solution 3P formulation at 40° C. at t= 6 months. HPLC Purity, Area % T = 6 m extra Peak @ peaks 33.8 min —3722 — (8.905%)(OO)

TABLE 20A Summary of results for the Solution 3P formulation at 60° C.Average Average HPLC Testing Particles Particles Purity, time, Solution3P Per Per Conc., Area % 60° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 0 N/A N/A N/A colorless 1¹Cloudy, 5.5 0 N/A N/A N/A then clears up after 5 min 3 6 Testing time,60° C. Peak 4, Peak 5, Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1min 13.6 min 16.8 min 20.5 min 20.9 min 37.7 min 0¹ N/A N/A N/A N/A N/AN/A 1¹ N/A N/A N/A N/A N/A 10919 (0.032%) 3 6 ¹Performed on HPLC10(PP)

TABLE 20A-1 Additional peaks for Solution 3P formulation at 60° C. at t= 1 month. HPLC Purity, Area % T = 6 m extra Peak @ peaks 3.1 min —190906 — (93.021%)(QQ)

TABLE 21A Summary of results for the Solution 4A formulation at 5° C.Average Average HPLC Testing Particles Particles Purity, time, Solution3A Per Per Conc., Area % 5° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 1.7 1436 4012 4102 colorless(0.002%) (0.006%) (0.007%) 1 3 6¹ Clear and 5.5 1.7 N/A 4220 5189colorless (0.007%) (0.009%) Testing time, 5° C. Peak 4, Peak 5, Peak 6,Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8 min 20.5 min20.9 min 37.7 min 0¹ 2436 5104 13313 61130 61955043 25823  (0.004%)(0.008%) (0.021%) (0.098%) (99.811%) (0.042%) 1 3 6¹ 1915 N/A N/A 5939859297216 7233 (0.003%) (0.100%) (99.829%) (0.012%) ¹Performed on HPLC10(RR)

TABLE 22A Summary of results for the Solution 4A formulation at 25° C.Average Average HPLC Testing Particles Particles Purity, time, Solution3A Per Per Conc., Area % 25° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 19.60 0.80 1.7 1609 4274 4316colorless (0.003%) (0.007%) (0.007%) 1¹ Clear and 5.5 1.7 2691 4756 5615colorless (0.004%) (0.008%) (0.009%) 3² Clear and 5.5 1.6 2867 516411833  colorless (0.004%) (0.010%) (0.025%) 6¹ Clear and 5.5 31.80 2.901.7 N/A 4892 6113 colorless (0.008%) (0.010%) Testing time, 25° C. Peak4, Peak 5, Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min16.8 min 20.5 min 20.9 min 37.7 min 0¹ 2568 4916 13545 62372 620351438603 (0.004%) (0.008%) (0.022%) (0.100%) (99.836%) (0.014%) 1¹ 2490 491812873 61607 61851541 18960  (0.004%) (0.008%) (0.021%) (0.099%)(99.813%) (0.031%) 3² 3338 5333  9917 62318 5339537 24907  (0.005%)(0.010%) (0.019%) (0.116%) (99.667%) (0.046%) 6¹ 2011 N/A N/A 5427459415139 5796 (0.003%) (0.091%) (99.836%) (0.010%) ¹Performed on HPLC10²Performed on HPLC12(SS)

TABLE 22A-1 Additional peaks for Solution 4A formulation at 25° C. at t= 1 month. HPLC Purity, Area % T = 1 m extra Peak @ peaks 36.6 min — 880— (0.001%)(TT)

TABLE 22A-2 Additional peaks for Solution 4A formulation at 25° C. at t= 3 months. HPLC Purity, T = 3 m extra Area % peaks Peak @ Peak @ Peak @Peak @ Peak @ 7.2 min 7.9 min 8.8 min 15.3 min 36.8 min 2566 13469 333813647 11556 (0.004%) (0.025%) (0.005%) (0.025%) (0.022%)(UU)

TABLE 23A Summary of results for the Solution 4A formulation at 40° C.Average Average HPLC Testing Particles Particles Purity, time, Solution3A Per Per Conc., Area % 40° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.6 73.00 14.00 1.7 1396 4399 4249colorless (0.002%) (0.007%) (0.007%) 1¹ Clear and 5.5 1.7 1444 6005 5383colorless (0.002%) (0.010%) (0.009%) 3² Clear and 5.5 1.6 9735 872512070  colorless (0.018%) (0.016%) (0.023%) 6¹ Clear and 5.5 64.10 3.401.7 2344 16305  3594 colorless (0.004%) (0.027%) (0.006%) Testing time,40° C. Peak 4, Peak 5, Peak 6, Peak 7, Capsaicin Peak 8, (months) 9.1min 13.6 min 16.8 min 20.5 min 20.9 min 37.7 min 0¹ 2491 5032 1352560955 61808714 4932 (0.004%) (0.008%) (0.022%) (0.098%) (99.843%)(0.008%) 1¹ 2371 4766 14950 64181 61911629 12508  (0.004%) (0.008%)(0.024%) (0.103%) (99.814%) (0.020%) 3² 3279 5247 13313 60741 5334331130494  (0.005%) (0.010%) (0.025%) (0.113%) (99.557%) (0.057%) 6¹ 3534N/A N/A 26386 59466240 5071 (0.006%) (0.044%) (99.792%) (0.009%)¹Performed on HPLC10 ²Performed on HPLC12(VV)

TABLE 23A-1 Additional peaks for Solution 4A formulation at 40° C. at t= 1 month. HPLC Purity, T = 1 m extra Area % peaks Peak @ Peak @ 5.9 min36.6 min 1982 1001 (0.003%) (0.002%)(WW)

TABLE 23A-2 Additional peaks for Solution 4A formulation at 40° C. at t= 3 months. HPLC Purity, T-3 m extra Area % peaks Peak @ Peak @ Peak @Peak @ Peak @ Peak @ Peak @ Peak @ Peak @ 4.8 min 4.9 min 5.5 min 5.7min 6.7 min 7.2 min 7.9 min 16.7 mm 38.3 mm 5243 2166 2835 5989 372710449 18748 9702 7206 (0.009%) (0.004%) (0.005%) (0.011%) (0.007%)(0.019%) (0.035%) (0.018%) (0.014%)(XX)

TABLE 23A-3 Additional peaks for Solution 4A formulation at 40° C. at t= 6 months. HPLC Purity, T = 6 m extra Area % peaks Peak @ Peak @ Peak @5.7 min 33.9 min 39.8 min 9446 2487 2507 (0.016%) (0.004%) (0.004%)(YY)

TABLE 24A Summary of results for the Solution 4A formulation at 60° C.Average Average HPLC Testing Particles Particles Purity, time, Solution3A Per Per Conc., Area % 60° C. Attribute Container Container HPLC Peak1, Peak 2, Peak 3, (months) Appearance pH 10.000 μm 25.000 μm (mg/ml)4.4 min 5.6 min 8.4 min 0¹ Clear and 5.5 1.7 1381 4731 4848 colorless(0.002%) (0.008%) (0.008%) 1¹ Clear and 5.6 1.7 6290 9546 1982 colorless(0.010%) (0.015%) (0.003%) 3 6 Testing time, 60° C. Peak 4, Peak 5, Peak6, Peak 7, Capsaicin Peak 8, (months) 9.1 min 13.6 min 16.8 min 20.5 min20.9 min 37.7 min 0¹ 2488 5365 12924 60663 61567424  8644 (0.004%)(0.009%) (0.021%) (0.098%) (99.828%) (0.014%) 1¹ 4376 4675 9876 6193161706951 11857 (0.007%) (0.008%) (0.016%) (0.100%) (99.391%) (0.019%) 36 ¹Performed on HPLC10(ZZ)

TABLE 24A-1 Additional peaks for Solution 4A formulation at 60° C. at t= 1 month. HPLC Purity, T = 1 m extra Area % peaks Peak @ 3.1 Peak @ 3.9Peak @ 5.0 Peak @ 5.1 Peak @ 5.56 Peak @ 5.9 Peak @ 6.9 Peak @ 7.4 Peak@ 9.0 min min min min min min min min min 158505 5348 6645 5154 1593511537 7720 8282 6672 (0.255%) (0.009%) (0.011%) (0.008%) (0.026%)(0.019%) (0.012%) (0.013%) (0.011%) HPLC Purity, Area % Peak @ 3.1 Peak@ 18.8 Peak @ 25.7 Peak @ 34.3 Peak @ 36.6 Peak @ 39.8 min min min minmin min 158505 9415 21701 3589 808 5264 (0.255%) (0.015%) (0.035%)(0.006%) (0.001%) (0.008%)

Example 3 Preparation of Additional Exemplary Capsaicin AqueousFormulations

Three additional exemplary stable aqueous capsaicin injectableformulations were prepared. Experimental procedures and results areprovided below.

Part I—Preparation of First Exemplary Additional Formulation

The formulation listed in the table below was prepared by the followingprocedure:

-   -   (a) Place 900 mL of water in a vessel;    -   (b) Add 6.80 grams of sodium acetate to the vessel containing        water;    -   (c) Adjust solution pH to 5.5 by adding 1N HCl;    -   (d) Add 10.0 grams of Kolliphor HS 15 to the solution [the        Kolliphor HS 15 has CAS Registry No 70142-34-6, and is a mixture        containing (a) about 70% (w/w) of a mixture

and (b) about 30% (w/w) polyethylene glycol; where the polyethyleneglycolyl has a weight-average molecular weight of about 660 g/mol; whichis sold and marketed by BASF as KOLLIPHOR® HS 15];

-   -   (e) Add 0.10 grams of dibutylhydroxytoluene to the solution, and        let the solution age for at least 2 hours;    -   (f) Add 0.25 grams of ethylenediaminetetraacetic acid        tetrasodium salt to the solution;    -   (g) Add 0.50 grams of trans-capsaicin to the solution, and age        the solution until the trans-capsaicin dissolves;    -   (h) Add 6.0 grams of NaCl to the solution;    -   (i) Adjust pH of the solution to pH=5.5 by adding 1N HCl or 1N        NaOH as needed;    -   (j) q.s. with water so the volume of the solution reaches 1        liter; and    -   (k) Sterile filter the solution.

Formulation An aqueous, capsaicin injectable formulation, comprising: a.0.05% (w/w) of trans-capsaicin; b. 1% (w/w) of a solubilizing agent,wherein the solubilizing agent is a mixture of

polyethylene glycol; wherein the polyethylene glycolyl has a weightaverage molecular weight of about 660 g/mol; c. 0.01% (w/w)dibutylhydroxytoluene; d. 0.68% (w/w) of sodium acetate or a mixture ofsodium acetate and acetic acid; e. 0.025% (w/w) ofethylenediaminetetraacetic acid or a salt thereof; f. 0.6% (w/w) ofsodium chloride; g. q.s. with water (i.e., least 97.6% (w/w)); andhaving a pH of 5.5.Part II—Preparation of Second Exemplary Additional Formulation

The formulation listed in the table below was prepared by the followingprocedure:

-   -   (a) Place 900 mL of water in a vessel;    -   (b) Add 3.40 grams of sodium acetate to the vessel containing        water;    -   (c) Adjust solution pH to 5.5 by adding 1N HCl;    -   (d) Add 10.0 grams of Kolliphor HS 15 to the solution [the        Kolliphor HS 15 has CAS Registry No 70142-34-6, and is a mixture        containing (a) about 70% (w/w) of a mixture of

and (b) about 30% (w/w) polyethylene glycol; where the polyethyleneglycolyl has a weight-average molecular weight of about 660 g/mol; whichis sold and marketed by BASF as KOLLIPHOR® HS 15];

-   -   (e) Add 0.10 grams of dibutylhydroxytoluene to the solution, and        let the solution age for at least 2 hours;    -   (f) Add 0.25 grams of ethylenediaminetetraacetic acid        tetrasodium salt to the solution;    -   (g) Add 0.50 grams of trans-capsaicin to the solution, and age        the solution until the trans-capsaicin dissolves;    -   (h) Add 7.5 grams of NaCl to the solution;    -   (i) Adjust pH of the solution to pH=5.5 by adding 1N HCl or 1N        NaOH as needed;    -   (j) q.s. with water so the volume of the solution reaches 1        liter; and    -   (k) Sterile filter the solution.

Formulation An aqueous, capsaicin injectable formulation, comprising: a.0.05% (w/w) of trans-capsaicin; b. 1% (w/w) of a solubilizing agent,wherein the solubilizing agent is a mixture of

polyethylene glycol; wherein the polyethylene glycolyl has a weightaverage molecular weight of about 660 g/mol; c. 0.01% (w/w)dibutylhydroxytoluene; d. 0.34% (w/w) of sodium acetate or a mixture ofsodium acetate and acetic acid; e. 0.025% (w/w) ofethylenediaminetetraacetic acid or a salt thereof; f. 0.75% (w/w) ofsodium chloride; g. q.s. with water (i.e., least 97.8% (w/w)); andhaving a pH of 5.5.Part III—Preparation of Third Exemplary Additional Formulation

The formulation listed in the table below was prepared by the followingprocedure:

-   -   (a) Place 900 mL of water in a vessel;    -   (b) Add 2.2 grams of trisodium citrate dihydrate to the vessel        containing water;    -   (c) Adjust solution pH to 5.5 by adding 1N HCl;    -   (d) Add 10.0 grams of Kolliphor HS 15 to the solution [the        Kolliphor HS 15 has CAS Registry No 70142-34-6, and is a mixture        containing (a) about 70% (w/w) of a mixture of

and (b) about 30% (w/w) polyethylene glycol; where the polyethyleneglycolyl has a weight-average molecular weight of about 660 g/mol; whichis sold and marketed by BASF as KOLLIPHOR® HS 15];

-   -   (e) Add 0.10 grams of dibutylhydroxytoluene to the solution, and        let the solution age for at least 2 hours;    -   (f) Add 0.25 grams of ethylenediaminetetraacetic acid        tetrasodium salt to the solution;    -   (g) Add 0.50 grams of trans-capsaicin to the solution, and age        the solution until the trans-capsaicin dissolves;    -   (h) Add 8.0 grams of NaCl to the solution;    -   (i) Adjust pH of the solution to pH=5.5 by adding 1N HCl or 1N        NaOH as needed;    -   (j) q.s. with water so the volume of the solution reaches 1        liter; and    -   (k) Sterile filter the solution.

Formulation An aqueous, capsaicin injectable formulation, comprising: a.0.05% (w/w) of trans-capsaicin; b. 1% (w/w) of a solubilizing agent,wherein the solubilizing agent is a mixture of

polyethylene glycol; wherein the polyethylene glycolyl has a weightaverage molecular weight of about 660 g/mol; c. 0.01% (w/w)dibutylhydroxytoluene; d. 0.22% (w/w) of sodium citrate or a mixture ofsodium citrate and citric acid; e. 0.025% (w/w) ofethylenediaminetetraacetic acid or a salt thereof; f. 0.8% (w/w) ofsodium chloride; g. q.s. with water (i.e., 97.9% (w/w) water); andhaving a pH of 5.5.

Example 4 Analysis of Capsaicin Solubility in Multiple AqueousFormulations Containing a Solubilizing Agent

Multiple aqueous formulations were prepared and analyzed to determinethe amount of dissolved capsaicin. The formulations contained differingamounts of the solubilizing agent Kolliphor HS 15 to increase the amountof capsaicin dissolved in the aqueous medium. The experimentalprocedures and results are described below.

Experimental Procedures

The equilibrium solubility of capsaicin was determined in a series ofaqueous solutions. Eight different solutions were prepared, as describedin Table 10 below, and the amount of dissolved capsaicin was determined.All eight solutions had a pH of 5.5. Kolliphor HS 15 has CAS RegistryNo. 70142-34-6, and is a mixture containing (a) about 70% (w/w) of amixture of

and (b) about 30% (w/w) polyethylene glycol; where the polyethyleneglycolyl has a weight-average molecular weight of about 660 g/mol; whichis sold and marketed by BASF as KOLLIPHOR® HS 15.

TABLE 10 Amount of Observed Kolliphor Dissolved HS 15 Capsaicin OtherComponents No. (w/v) (mg/mL) (w/v) 1 1% 0.958 0.9% NaCl, 0.1% EDTA,0.01% butylated hydroxytoluene, and 20 mM Citrate Buffer. 2 2% 1.68 0.9%NaCl, 0.1% EDTA, 0.01% butylated hydroxytoluene, and 20 mM CitrateBuffer. 3 4% 2.47 0.9% NaCl, 0.1% EDTA, 0.01% butylated hydroxytoluene,and 20 mM Citrate Buffer. 4 5% 3.76 0.9% NaCl, 0.1% EDTA, 0.01%butylated hydroxytoluene, and 20 mM Citrate Buffer. 5 1% 1.05 5%Dextrose, 0.1% EDTA, 0.01% butylated hydroxytoluene, and 20 mM CitrateBuffer. 6 2% 1.70 5% Dextrose, 0.1% EDTA, 0.01% butylatedhydroxytoluene, and 20 mM Citrate Buffer. 7 4% 2.67 5% Dextrose, 0.1%EDTA, 0.01% butylated hydroxytoluene, and 20 mM Citrate Buffer. 8 5%3.78 5% Dextrose, 0.1% EDTA, 0.01% butylated hydroxytoluene, and 20 mMCitrate Buffer.

Example 5 Twenty-Six Month Stability Analysis for Exemplary Formulations

The formulations in Table 11 below were subjected to stability analysisby storage for twenty-six (26) months at the conditions specified below(i.e., 25° C. at 60% relative humidity, or 40° C. at 75% relativehumidity), followed by analytical analysis to determine the amount oftrans-capsaicin and any detectable impurities in the formulation.Results are presented in Tables 12-15 below.

The abbreviation BHT refers to dibutylhydroxytoluene. The abbreviation“EDTA” refers to ethylenediaminetetraacetic acid. The abbreviation “ND”refers to not detected. The Kolliphor HS-15 has CAS Registry No70142-34-6, and is a mixture containing (a) about 70% (w/w) of a mixtureof

and (b) about 30% (w/w) polyethylene glycol; where the polyethyleneglycolyl has a weight-average molecular weight of about 660 g/mol; whichis sold and marketed by BASF as KOLLIPHOR® HS 15. The phrase “AverageParticles Per Container” refers to the average number of particlesobserved in a container, where the container held approximately 1.5 mLof aqueous formulation to be analyzed. Dimer 1 Impurity has thefollowing chemical structure:

Dimer 2 Impurity is believed to have one of the following chemicalstructures:

5-Oxo-capsaicin has the following chemical structure:

TABLE 11 Formulation 1A Formulation 2A 1 mg/mL trans-capsaicin 2 mg/mLtrans-capsaicin 2% (wt/wt) Kolliphor HS-15 4% (wt/wt) Kolliphor HS-15 20mM citrate buffer 20 mM citrate buffer 0.1% (wt/wt) disodium EDTA 0.1%(wt/wt) disodium EDTA 0.01% (wt/wt) BHT 0.01% (wt/wt) BHT 0.625% (wt/wt)NaCl 0.625% (wt/wt) NaCl q.s. water q.s. water

TABLE 12 Summary of Results from Storage of Formulation 1A for 26 Monthsat 25° C./60% Relative Humidity Observed Result at Observed Result atAnalytical Feature Time = 0 Months Time = 26 Months Appearance clear andcolorless clear and colorless pH of the solution 5.5 5.35 Average Numberof Particles 19.4 583 Having Size ≥10 μM Per Container Average Number ofParticles 1.1 235 Having Size ≥25 μM Per Container Concentration oftrans- 1.0 0.99 capsaicin (mg/mL) as determined by HPLC analysisConcentration of BHT Not tested 0.0108 (mg/mL) Purity Analysis by HPLCDetected Amount According to Percent Analyte Area of HPLC Plot (area %)Impurity at RRT 0.27 in 0.01 ND HPLC Plot 5-oxo-capsaicin 0.01 0.06Impurity at RRT 0.80 in 0.02 0.06 HPLC Plot cis-capsaicin 0.01 0.08trans-capsaicin 99.80 99.8  Dimer 1 Impurity 0.02 ND Dimer 2 Impurity NDND

TABLE 13 Summary of Results from Storage of Formulation 1A for 26 Monthsat 40° C./75% Relative Humidity Observed Result at Observed Result atAnalytical Feature Time = 0 Months Time = 26 Months Appearance clear andcolorless slightly opaque, no visible particles pH of the solution 5.55.40 Average Number of Particles 45.8 583 Having Size ≥10 μM PerContainer Average Number of Particles 2.0 235 Having Size ≥25 μM PerContainer Concentration of trans- 1.0 1.0 capsaicin (mg/mL) asdetermined by HPLC analysis Concentration of BHT Not tested 0.0108(mg/mL) Purity Analysis by HPLC Detected Amount According to PercentAnalyte Area of HPLC Plot (area %) Impurity at RRT 0.27 in 0.01 ND HPLCPlot 5-oxo-capsaicin 0.01 0.06 Impurity at RRT 0.80 in 0.02 0.06 HPLCPlot cis-capsaicin 0.01 0.09 trans-capsaicin 99.80 99.75 Dimer 1Impurity 0.02 0.02 Dimer 2 Impurity ND 0.01

TABLE 14 Summary of Results from Storage of Formulation 2A for 26 Monthsat 25° C./60% Relative Humidity Observed Result at Observed Result atAnalytical Feature Time = 0 Months Time = 26 Months Appearance clear andcolorless clear and colorless pH of the solution 5.6 5.41 Average Numberof Particles 16.6 759 Having Size ≥10 μM Per Container Average Number ofParticles 0.4 611 Having Size ≥25 μM Per Container Concentration oftrans- 1.7 1.7 capsaicin (mg/mL) as determined by HPLC analysisConcentration of BHT Not tested 0.010 (mg/mL) Purity Analysis by HPLCDetected Amount According to Percent Analyte Area of HPLC Plot (area %)Impurity at RRT 0.27 in 0.01 ND HPLC Plot 5-oxo-capsaicin 0.01 0.04Impurity at RRT 0.80 in 0.02 0.07 HPLC Plot cis-capsaicin 0.10 0.09trans-capsaicin 99.82 99.79 Dimer 1 Impurity 0.003 0.01 Dimer 2 ImpurityND ND

TABLE 15 Summary of Results from Storage of Formulation 2A for 26 Monthsat 40° C./75% Relative Humidity Observed Result at Observed Result atAnalytical Feature Time = 0 Months Time = 26 Months Appearance clear andcolorless Slightly opaque, no visible particles pH of the solution 5.65.40 Average Number of Particles 10.9 3471 Having Size ≥10 μM PerContainer Average Number of Particles 0.8 458 Having Size ≥25 μM PerContainer Concentration of trans- 1.7 1.7 capsaicin (mg/mL) asdetermined by HPLC analysis Concentration of BHT Not tested 0.010(mg/mL) Purity Analysis by HPLC Detected Amount According to PercentAnalyte Area of HPLC Plot (area %) Impurity at RRT 0.27 in 0.006 ND HPLCPlot 5-oxo-capsaicin 0.005 0.03 Impurity at RRT 0.80 in 0.018 0.07 HPLCPlot cis-capsaicin 0.088 0.09 trans-capsaicin 99.83 99.71 Dimer 1Impurity 0.01 0.08 Dimer 2 Impurity ND 0.02

Example 6 Preparation of Additional Exemplary Capsaicin AqueousFormulation

The aqueous capsaicin injectable formulation labeled as CapsaicinFormulation 1 in the following table was prepared. Experimentalprocedures are provided below.

Capsaicin Formulation 1 An aqueous, capsaicin injectable formulationcontaining: a. 0.05% (w/w) of trans-capsaicin; b. 1% (w/w) of macrogol15 hydroxystearate; c. 0.01% (w/w) dibutylated hydroxytoluene; d. 50 mMof buffer that is a mixture of sodium acetate and acetic acid; e. 0.025%(w/w) of ethylenediaminetetraacetic acid or a salt thereof; f. 0.6%(w/w) of sodium chloride; g. q.s. with water (i.e., about 97.6% (w/w));and having a pH of 5.5.Experimental Procedures

Butylated hydroxytoluene (BHT) and macrogol 15 hydroxystearate are addedand slightly warmed (to facilitate melting) and then mixed untildissolved to provide a BHT/Macrogol solution.

In a separate container, ethylenediaminetetraacetic acid (EDTA) isdissolved in water for injection (WFI). The resulting EDTA/WFI solutionis added to the BHT/Macrogol solution while mixing. To the resultingsolution is added trans-capsaicin and the resulting mixture is mixed fora minimum of 4 hours until a uniform solution is achieved (hereinafter“Capsaicin Solution”).

In a separate container, sodium acetate trihydrate and sodium chlorideare dissolved in WFI and the pH of the solution is adjusted to a pH ofabout 5.5. To this solution is added the necessary amount of CapsaicinSolution and the resulting solution is adjusted to weight with WFI. ThepH is measured and adjusted with hydrochloric acid as necessary toachieve a pH of 5.5±0.05. The resulting solution is mixed to assurehomogeneity. Then, the solution is aseptically filtered through two 0.2micron sterilizing filters that are tested both before use and after usefor integrity, to thereby provide Capsaicin Formulation 1.

Macrogol 15 hydroxystearate has CAS Registry No 70142-34-6, and is amixture containing (a) about 70% (w/w) of a mixture of

and (b) about 30% (w/w) polyethylene glycol; where the polyethyleneglycolyl has a weight-average molecular weight of about 660 g/mol; whichis sold and marketed by BASF as KOLLIPHOR® HS 15.

Example 7 Assessment of Toxicity for Exemplary Capsaicin FormulationUpon Administration to Rabbits

An aliquot of Capsaicin Formulation A was subjected to toxicityevaluation in rabbits. Experimental Procedures and results are providedbelow.

Part I—Experimental Procedures for Toxicity Analysis in Rabbits

An aliquot of Capsaicin Formulation A was administered as a single dosevia intraarticular injection to rabbits, and analysis was performed tocheck for evidence of toxicity. Capsaicin Formulation A was preparedbased on procedures described above for Capsaicin Formulation 1, and adescription of Capsaicin Formulation A is provided in the followingtable.

Capsaicin Formulation A An aqueous, capsaicin injectable formulationcontaining: a. 0.05% (w/w) of trans-capsaicin; b. 1% (w/w) of macrogol15 hydroxystearate; c. 0.01% (w/w) dibutylated hydroxytoluene; d. 50 mMof buffer that is a mixture sodium acetate and acetic acid; e. 0.025%(w/w) of ethylenediaminetetraacetic acid or a salt thereof; f. 0.6%(w/w) of sodium chloride; g. q.s. with water (i.e., about 97.6% (w/w));and having a pH of 5.5.Procedurally, thirteen male and fourteen female New Zealand Whiterabbits were received from Covance Research Products, Inc. (Denver,Pennsylvania). Animals were acclimated to the test facility for 14 daysprior to initiation. At initiation of dosing, animals were 6 to 7 monthsold, and body weights ranged from 3060 g to 3587 g for males and 2923 to3527 g for females. Animals not used in the study were removed from thestudy room. Males were individually housed in stainless steel cageswithout plastic bottoms. When possible, females were pair-housed instainless steel cages, with plastic bottoms. Animals were individuallyhoused during the pre-dose phase (females pair-housed upon arrival), andfor behavior reasons. Water was provided ad libitum. Upon receipt,animals were presented with increasing amounts of Certified Rabbit Diet#5325 (PMI NUTRITION INTERNATIONAL CERTIFIED LABDIET®) once daily duringthe first week following arrival until acclimated to approximately 150g/day. Animals were maintained on approximately 150 g/day of CertifiedRabbit Diet #5325 until study termination.

The male and female New Zealand White rabbits were assigned to threegroups, and doses of Capsaicin Formulation A were administered asindicated in the following table.

Concentration Dose of trans- Dose of Capsaicin No. of Animals CapsaicinVolume in the Dose Group Male Female (mg) (mL) (mg/mL) 1 4 4 0 0.6 0(control) 2 4 4 0.1 0.2 0.5 3 4 4 0.3 0.6 0.5

Animals were administered a single dose of test article (i.e., CapsaicinFormulation A, or placebo) on Day 1 via intra-articular injection intothe right stifle joint. Dosing was followed by an observation period of4 weeks. The vehicle control article (i.e., placebo) was the same asCapsaicin Formulation A except that it did not contain capsaicin. Priorto injection of test article, animals were sedated via gas anesthesiawith sevoflurane. The gas was administered by designated techniciansusing a nose cone. Following anesthesia but prior to intra-articularinjection, the injection site was prepared aseptically with three ormore chlorhexidine scrubs, wiping with sterile water between each scrub.Animals were administered 1 mg/kg of midazolam and 0.6 mg/kg ofmeloxicam SR subcutaneously prior to gas anesthesia. A bland ophthalmicointment was applied to both eyes, and the right stifle joint area wasclipped free of hair. Animals were positioned in dorsal recumbency, withthe leg held up to allow for surgical scrub. The arthrocentesis site wasprepared aseptically with three chlorhexidine scrubs, wiping withsterile water between each scrub. The right stifle joint was flexedprior to positioning the joint at an approximate 90° angle with onehand. The patella was located, and the appropriate site forarthrocentesis was palpated with a sterile, gloved hand. A 25 G×⅝ inchneedle (25 G to 23 G depending on the test article) was used to enterthe joint midway between the proximal aspect of the patella and thetibial tuberosity on the lateral side of the stifle joint. The needlewas directed toward the intercondylar space to a depth of approximately7 to 10 mm and the appropriate volume (up to 0.6 mL) of test articlewere delivered. The stifle joint was then flexed several times. Then,the animal was placed on a warm water circulating blanket, and a blandophthalmic ointment was applied during recovery. Buprenorphine SR (0.2mg/kg) was administered via subcutaneous (SQ) injection between theshoulder blades during recovery. The animal was monitored for pain anddiscomfort during recovery and was returned to its home cage aftercomplete recovery. An Elizabethan collar was positioned on animalschewing at dose sites, when needed. Additional pain management ofanimals was monitored by veterinary staff.

Assessment of toxicity was based on mortality, clinical observations(including qualitative food consumption), body weights, physicalexaminations, and clinical and anatomic pathology. Blood samples werecollected for toxicokinetic evaluation. In particular, blood samples(approximately 0.5 mL) were collected via a jugular vein or medialauricular ear artery of the animals on Day 1 of the dosing phase.Samples were generally collected pre-dose and approximately 15 and 30minutes and 1, 2, 4, 8, and 24 hours post-dose. Animals were not fastedfor sample collections. Blood was collected into tubes containingpotassium (K2) EDTA as the anticoagulant. Samples were maintained onchilled cryoracks prior to and after centrifugation. Samples weregenerally centrifuged within 1 hour of collection. Plasma was harvestedand placed on dry ice until stored in a freezer, set to maintain attemperature in the range of −60° C. to −80° C. Samples remained storeduntil shipped on dry ice to a laboratory for analysis. Plasma sampleswere analyzed for capsaicin content. Toxicokinetic analysis wasperformed, which included analysis of Cmax, dose normalized maximumconcentration (DN Cmax), Tmax, area under the curve from time 0 to thetime of the last measurable concentration (calculated using the lineartrapezoidal rule), area under the curve from time 0 to 24 hours(calculated using the linear trapezoidal rule), and eliminationhalf-life. On the day of dosing, cageside observations were conductedfor each animal at approximately 1, 4, and 8 hours post-dose. Post-doseobservation start times were based on the dosing completion time foreach animal. Abnormal findings or an indication of normal were recorded.Body weights were recorded twice during the pre-dose phase and on Days1, 8, 15, and 22 of the dosing phase. Qualitative food consumption wasrecorded once daily (except on day of animal arrival) during thepre-dose and dosing phases; abnormal findings were recorded. Physicalexaminations were conducted once during the pre-dose phase and once Week1 of the dosing phase; animals were examined by a Veterinarian/technicalstaff

On Day 29 of the dosing phase, all animals were anesthetized with sodiumpentobarbital, exsanguinated, and necropsied. Animals were not fastedprior to terminal procedures. Terminal body weights were recorded. Amacroscopic examination of the external features of the carcass;external body orifices; abdominal, thoracic, and cranial cavities;organs; and tissues was performed. Organ weights were recorded at thescheduled sacrifice. Bone marrow smears (two slides) were prepared fromthe femur of each animal at scheduled sacrifices. All animals survivedto the scheduled necropsy

Synovial fluid from the knee of each animal was collected at scheduledsacrifices for cytological examination. A study-specific procedure wasfollowed during collection of synovial fluid and was as follows. Theanimal was anesthetized with sodium pentobarbital and placed in dorsalrecumbency. Hair was clipped if needed. The knee was wiped withisopropyl alcohol, and skin was cut away to expose the joint. The kneewas positioned by a second restrainer at an approximate 90° angle,keeping the femur and tibia aligned and the knee straight. A 23 G×¾inch×7 inch (0.6×19 mm×178 mm) needle was attached to a syringe. Thesynovial fluid was collected from the right femorotibial joint. Thepatella was located and palpated as the joint was entered midway betweenthe proximal aspect of the patella and the tibial tuberosity on thelateral side. The needle was advanced with a slight angle in toward theintercondylar space. The syringe was pulled to approximately 2 mL whenentering the capsule joint. The needle was advanced until entering intothe membrane containing synovial fluid, which allowed the synovial fluidto enter the tubing. The pressure was released from the syringe toprevent pulling the sample into the syringe prior to the removal of theneedle. The sample was then placed in a vial, and the tubing was clearedof the sample by using a pistol of a 50 μL pipette tip and pushingthrough the tubing. Samples were placed on wet ice until two synovialfluid smears were made, and the weight was then recorded. The remainingfluid was stored in a freezer, set to maintain at a temperature in therange of −60° C. to −80° C. Samples were subjected to cytologicalexamination.

Part II—Results of Toxicity Analysis in Rabbits

No significant local or systemic adverse effects were observedattributable to administration of up to a 0.3 mg dose of trans-capsaicinby administration of Capsaicin Formulation A once on Day 1 of the dosingphase via intra-articular injection to the stifle joint of rabbits. Theobserved effects of administering Capsaicin Formulation A were limitedto (i) mildly increased numbers of neutrophils (heterophils) andmononuclear cells in the synovial fluid of most animals administeredtrans-capsaicin at a dose of 0.1 mg or 0.3 mg, and (ii) minimallydecreased total protein concentration, due to minimally decreasedalbumin concentration, in males administered trans-capsaicin at a doseof 0.3 mg, and (iii) minimally increased myxoid material in the synoviumof the stifle joint, though this finding was considered nonadverse. Noeffects on hematology or coagulation were identified due toadministration of Capsaicin Formulation A. No difference in macroscopicfindings or organ weights was observed due to administration ofCapsaicin Formulation A. No alteration in body weight or body weightgain was observed due to administration of Capsaicin Formulation A. Noabnormalities were observed during physical examination due toadministration of Capsaicin Formulation A.

Based on results from this experiment, the high-dose level of 0.3 mgtrans-capsaicin is the no observed adverse effect level (NOAEL). At atrans-capsaicin dose level of 0.3 mg administered in the form ofCapsaicin Formulation A, the Day 1 combined (males and females) meanCmax and AUC₀₋₂₄ values for trans-capsaicin were 37.9 ng/mL and 27.8ng·h/mL, respectively.

Example 8 Assessment of Toxicity for Exemplary Capsaicin FormulationUpon Administration to Dogs

An aliquot of Capsaicin Formulation A was subjected to toxicityevaluation in purebred beagle dogs. Experimental Procedures and resultsare provided below.

Part I—Experimental Procedures for Toxicity Analysis in Purebred BeagleDogs

An aliquot of test article (i.e., placebo (control) or CapsaicinFormulation A) was administered as a single dose via intraarticularinjection to dogs, and analysis was performed to check for evidence oftoxicity. Capsaicin Formulation A was prepared based on proceduresdescribed above for Capsaicin Formulation 1, and a description ofCapsaicin Formulation A is provided in the following table.

Capsaicin Formulation A An aqueous, capsaicin injectable formulationcontaining: a. 0.05% (w/w) of trans-capsaicin; b. 1% (w/w) of macrogol15 hydroxystearate; c. 0.01% (w/w) dibutylated hydroxytoluene; d. 50 mMof buffer that is a mixture of sodium acetate and acetic acid; e. 0.025%(w/w) of ethylenediaminetetraacetic acid or a salt thereof; f. 0.6%(w/w) of sodium chloride; g. q.s. with water (i.e., about 97.6% (w/w));and having a pH of 5.5.Procedurally, male and female purebred beagle dogs were received fromCovance Research Products, Inc. in Cumberland, Virginia. Animals wereacclimated to the test facility for 20 days (males) and 24 days(females) prior to initiation. At initiation of dosing, animals were 7to 8 months old, and body weights ranged from 7.4 to 11.8 kg for malesand 6.5 to 9.2 kg for females. Animals not used on study were placed inthe stock colony. Animals were housed in stainless steel cages withTenderfoot® flooring. Animals were socially housed by sex, unlessindividually housed during parts of the pre-dose phase, forstudy-related procedures, or for individual assessment of foodconsumption. Water was provided ad libitum. Animals were offeredCertified Canine Diet #5007 (PMI NUTRITION INTERNATIONAL CERTIFIEDLABDIET®); it was provided for 4 to 5 hours each day, unless otherwisespecified. Feed was offered following the completion of dosing for eachroom on the day of dosing or at approximately the same time as theexpected start of dosing (±2 hours) on days without dosing. Foracclimation purposes, animals had access to feed for longer than 4 to 5hours on the day of and the day after arrival. Beginning on Day 16 ofthe dosing phase for females, one animal (Group 3 female) was givencanned food once daily.

The male and female dogs were assigned to groups and doses of testarticled (i.e., placebo (control) or Capsaicin Formulation A) wereadministered as indicated in the following table.

Concentration Dose of Dose of Capsaicin No. of Animals Capsaicin Volumein the Dose Group Male Female (mg) (mL) (mg/mL) 1 4 4 0 2 0 (control) 24 4 0.1 0.2 0.5 3 4 4 0.3 0.6 0.5 4 4 4 1 2 0.5Animals were administered a single dose of test article (i.e., placebo(control) or Capsaicin Formulation A) on Day 1 via intra-articularinjection into the stifle joint. Dosing was followed by an observationperiod of 4 weeks. The vehicle control article (i.e., placebo) was thesame as Capsaicin Formulation A except that it did not containcapsaicin. Prior to injection of test article, animals were fasted forthe overnight period prior to dosing. Additionally, animals werepre-treated with an intra-articular injection of lidocaine into theright stifle joint on Day 1 of the dosing phase, prior to doseinitiation. Animals were anesthetized for administration of lidocaine,which was administered as follows for each group:

Lidocaine Volume Lidocaine Group (mL) Concentration 1 0.5 4% (control) 22.0 1% 3 1.5 1% 4 0.5 4%Feed was returned following the completion of dosing.

Assessment of toxicity was based on mortality, clinical observations,body weights, food consumption, electrocardiography (ECG), synovialfluid collection, and clinical and anatomic pathology. Blood samples(approximately 2.0 mL) were collected via the jugular or cephalic veinon Day 1 of the dosing phase (see Protocol Deviations). Samples werecollected pre-dose and approximately 15 and 30 minutes and 1, 2, 4, 8,and 24 hours post-dose. Animals were not fasted for sample collections,unless fasted for other study procedures. Blood was collected into tubescontaining potassium (K2) EDTA as the anticoagulant. Samples weremaintained on chilled cryoracks prior and were centrifuged within 1 hourof collection. Plasma was harvested and divided into two approximatelyaliquots and placed on dry ice, then stored in a freezer set to maintainat a temperature in the range of −60° C. to −80° C., until shipped.Aliquot 1 was shipped on dry ice to the testing laboratory for analysisand Aliquot 2 was retained as backup at the testing facility. Plasmasamples were analyzed for capsaicin. Toxicokinetic analysis wasperformed, which included analysis of Cmax, dose normalized maximumconcentration (DN Cmax), Tmax, area under the curve from time 0 to thetime of the last measurable concentration (calculated using the lineartrapezoidal rule), area under the curve from time 0 to 24 hours(calculated using the linear trapezoidal rule), and eliminationhalf-life. Cageside observations were conducted for each animal oncedaily during the pre-dose and dosing phases, except on days whendetailed observations were conducted. Abnormal findings were recorded.Detailed observations were conducted for each animal three times formales and four times for females during the pre-dose phase and on Days1, 8, 15, 22, and 28 of the dosing phase. Detailed observations werealso collected for each animal on the day of scheduled sacrifice (allsurviving animals). Abnormal findings or an indication of normal wasrecorded. Unscheduled observations were recorded. On the day of dosing,cage-side observations were conducted for each animal at approximately1, 4, and 8 hours post-dose. Post-dose observation start times for eachanimal were based on the dosing completion time for each animal.Abnormal findings or an indication of normal was recorded. Body weightswere recorded three times for males and four times for females duringthe pre-dose phase and on Days 1, 8, 15, 22, 28 (females only), and 29(males only) of the dosing phase. Quantitative food consumption wasrecorded weekly (unless fasted for other study procedures) to Week 4 andfrom Days 22 to 28 of the dosing phase. Electrocardiograms (ECGs) wererecorded once during the pre-dose phase and once during Week 4 of thedosing phase. Electrocardiograms were recorded using eight leads. Bloodsamples for hematology, coagulation, and clinical chemistry werecollected from fasted animals via a jugular or cephalic vein. Bloodsamples were collected twice during the pre-dose phase, on Day 2 of thedosing phase, and on the day of scheduled sacrifice. Urine samples forurinalysis were collected chilled during the overnight period beforeblood collection from animals fasted overnight. Urine samples werecollected once during the pre-dose phase, on Day 2 of the dosing phase,and on the day of scheduled sacrifice. Synovial fluid was collected fromthe knee of all animals on the day of scheduled sacrifice.

On Day 29 of the dosing phase, all animals, having been fastedovernight, were anesthetized with sodium pentobarbital, exsanguinated,and necropsied. Terminal body weights were recorded for sacrificedanimals. A macroscopic examination of the external features of thecarcass; external body orifices; abdominal, thoracic, and cranialcavities; organs; and tissues was performed. Organ weights were recordedat the scheduled sacrifice. Paired organs were weighed together. Bonemarrow smears (two slides) were prepared from the sternum of each animalat scheduled sacrifices.

Part II—Results of Toxicity Analysis in Dogs

No significant local or systemic adverse effects were observedattributable to administration of up to 1 mg dose of trans-capsaicinusing Capsaicin Formulation A once on Day 1 of the dosing phase viaintra-articular injection to the stifle joint of dogs. The observedeffects of administering Capsaicin Formulation A were limited to (i) aminimally to mildly increased number of reactive mononuclear cells inthe synovial fluid of the injected stifle, (ii) minimal to slighthypertrophy/hyperplasia and erosion/ulceration and minimal hemorrhageand degeneration of the synovium, and (iii) minimal pigment in thesynovium of one female administered a 1 mg dose of trans-capsaicin usingCapsaicin Formulation A. No alteration in body weight or body weightgain was observed attributable to administration of CapsaicinFormulation A. No effect on food consumption was observed attributableto administration of Capsaicin Formulation A. No test article-relatedchange in PR interval, QRS duration, QT interval, corrected QT (QTc)interval, or heart rate was observed on Day 23 (males) or 25 (females)of the dosing phase in animals administered 0.1, 0.3, or 1 mg oftrans-capsaicin via Capsaicin Formulation A. No abnormal ECG waveformsor arrhythmias attributed to Capsaicin Formulation A were observedduring qualitative assessment of the ECGs. No effects on hematology,clinical chemistry, coagulation, or urinalysis tests were identifiedattributable to administration of Capsaicin Formulation A. Minimally tomildly increased total white blood cell count, due to increased absoluteneutrophil and/or monocyte counts, and minimally increased fibrinogenconcentration were noted on Day 2 in most animals of all groups,including controls, and were considered secondary to study procedures.No effect on organ weight parameters attributable to CapsaicinFormulation A was observed.

Based on these results, the high-dose level of 1 mg of trans-capsaicinadministered via Capsaicin Formulation A is the no observed adverseeffect level (NOAEL). At a dose level of 1 mg trans-capsaicinadministered in the form of Capsaicin Formulation A, the Day 1 combined(males and females) mean C_(max) and AUC₀₋₂₄ values for trans-capsaicinwere 9.21 ng/mL and 21.7 ng·h/mL, respectively.

Example 9 Autoclave Steam Sterilization of an Exemplary CapsaicinFormulation

An aliquot of Capsaicin Formulation A was placed into a container andsubjected to autoclave steam sterilization. Capsaicin Formulation A wasprepared based on procedures described above for Capsaicin Formulation1, and a description of Capsaicin Formulation A is provided in thefollowing table.

Capsaicin Formulation A An aqueous, capsaicin injectable formulationcontaining: a. 0.05% (w/w) of trans-capsaicin; b. 1% (w/w) of macrogol15 hydroxystearate; c. 0.01% (w/w) dibutylated hydroxytoluene; d. 50 mMof buffer that is a mixture of sodium acetate and acetic acid; e. 0.025%(w/w) of ethylenediaminetetraacetic acid or a salt thereof; f. 0.6%(w/w) of sodium chloride; g. q.s. with water (i.e., about 97.6% (w/w));and having a pH of 5.5.

Experimental Procedures and results are provided below.

Part I—Experimental Procedure for Sterilization Process Providing aF₀-Value in the Range of 8.8 to 8.9

An aliquot of Capsaicin Formulation A was placed into a sealedcontainer. The sealed container containing Capsaicin Formulation A wasthen placed into an autoclave and subjected to sterilization conditionsto achieve an F₀-value in the range of 8.8 to 8.9. The sterilizationconditions involving heating the sterilization chamber of the autoclaveto a temperature in the range of 121.7° C. to 122.0° C. and a pressureof about 3.4 barr, holding at the aforementioned conditions for aduration of about 7 minutes, and then returning the autoclave chamber toambient temperature and pressure. Thereafter, an aliquot of thesterilized Capsaicin Formulation A was analyzed by HPLC, and the HPLCchromatogram compared to the HPLC chromatogram of an aliquot ofCapsaicin Formulation A that had not undergone the sterilizationprocedure.

Part II—Results

HPLC analysis of the aliquot of Capsaicin Formulation A subjected to theabove sterilization revealed that there was no significant loss ofcapsaicin due to the sterilization procedure. The Capsaicin FormulationA was found to be stable to the sterilization conditions.

Part III—Experimental Procedure for Sterilization Process Providing aF₀-Value in the Range of 25.7 to 26.1

An aliquot of Capsaicin Formulation A was placed into a sealedcontainer. The sealed container containing Capsaicin Formulation A wasthen placed into an autoclave and subjected to sterilization conditionsto achieve an F₀-value in the range of 25.7 to 26.1. The sterilizationconditions involving heating the sterilization chamber of the autoclaveto a temperature in the range of 121.0° C. to 123.0° C. and pressure ofabout 3.4 barr, holding at the aforementioned conditions for a durationof about 22 minutes, and then returning the autoclave chamber to ambienttemperature and pressure. Thereafter, an aliquot of the sterilizedCapsaicin Formulation A was analyzed by HPLC.

Part IV—Results

HPLC analysis of the aliquot of Capsaicin Formulation A subjected to theabove sterilization revealed that there was no significant loss ofcapsaicin due to the sterilization procedure. The Capsaicin FormulationA was found to be stable to the sterilization conditions.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

What is claimed is:
 1. A compound having the formula:


2. A formulation comprising a compound of claim 1 and capsaicin.
 3. Theformulation of claim 2, wherein a 2 mL aliquot of the formulationcontains less than 6000 particles having an average diameter of ≥10 μm.4. The formulation of claim 2, wherein a 2 mL aliquot of the formulationcontains less than 3000 particles having an average diameter of ≥10 μm.5. The formulation of claim 2, wherein a 2 mL aliquot of the formulationcontains less than 2000 particles having an average diameter of ≥10 μm.6. The formulation of claim 2, wherein a 2 mL aliquot of the formulationcontains less than 1000 particles having an average diameter of ≥10 μm.7. The formulation of claim 2, wherein a 2 mL aliquot of the formulationcontains less than 500 particles having an average diameter of ≥10 μm.8. The formulation of claim 2, wherein a 2 mL aliquot of the formulationcontains less than 200 particles having an average diameter of ≥10 μm.9. The formulation of claim 2, wherein a 2 mL aliquot of the formulationcontains less than 100 particles having an average diameter of ≥10 μm.10. The formulation of claim 2, wherein a 2 mL aliquot of theformulation that has been stored at 25° C. and 60% Relative Humidity fora duration of 3 months contains less than 6000 particles having anaverage diameter of ≥10 μm.
 11. The formulation of claim 2, wherein a 2mL aliquot of the formulation that has been stored at 25° C. and 60%Relative Humidity for a duration of 3 months contains less than 3000particles having an average diameter of ≥10 μm.
 12. The formulation ofclaim 2, wherein a 2 mL aliquot of the formulation that has been storedat 25° C. and 60% Relative Humidity for a duration of 3 months containsless than 1000 particles having an average diameter of ≥10 μm.
 13. Theformulation of claim 2, wherein a 2 mL aliquot of the formulation thathas been stored at 25° C. and 60% Relative Humidity for a duration of 3months contains less than 500 particles having an average diameter of≥10 μm.